<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03837470</url>
  </required_header>
  <id_info>
    <org_study_id>IRB_00112270</org_study_id>
    <nct_id>NCT03837470</nct_id>
  </id_info>
  <brief_title>Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction</brief_title>
  <acronym>ERES-HFpEF</acronym>
  <official_title>Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Adhish Agarwal</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Utah Center for Clinical and Translational Science</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Heart failure (HF) affects 2-3% of the population, and is characterized by impaired sodium&#xD;
      balance which results in fluid overload. Ejection fraction, a measure of systolic function,&#xD;
      is reduced in only about half of all HF patients. Incidence of heart failure with preserved&#xD;
      ejection fraction (HFpEF) has increased in the last 20 years making it a growing public&#xD;
      health problem. Currently, most patients admitted to the hospital with heart failure have&#xD;
      preserved rather than reduced ejection fractions. However, to date it remains unknown why&#xD;
      patients with HFpEF retain salt and water. The hypothesis is that patients with clinical&#xD;
      HFpEF have an impaired renal response to salt loading, intravascular expansion and diuretics.&#xD;
      Characterization of the salt and water excretory renal response to intravascular salt, fluid&#xD;
      and diuretic load in patients with HFpEF will provide insight into the pathophysiology of&#xD;
      HFpEF, and may help in the development of novel strategies to target renal sodium handling in&#xD;
      patients with HFpEF. This characterization is the primary objective of this pilot project.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In patients with heart failure with reduced ejection fraction (HFrEF), poor renal perfusion&#xD;
      and neuro-hormonal activation cause renal salt and water retention. In contrast to HFrEF,&#xD;
      patients with HFpEF have blunted neuro-hormonal activation, and other mechanisms likely cause&#xD;
      fluid overload. Investigators have proposed several mechanisms including inflammatory state,&#xD;
      endothelial dysfunction, decreased vascular compliance, pulmonary hypertension, and reduced&#xD;
      nitric oxide (NO) bioavailability. However, the etiology and pathophysiology of fluid&#xD;
      overload in HFpEF patients remains controversial.&#xD;
&#xD;
      Renal dysfunction is common in patients with HFpEF, and is associated with cardiac&#xD;
      remodeling. HFpEF is associated with coronary microvascular endothelial activation and&#xD;
      oxidative stress, which through reduction of NO dependent signaling contributes to the high&#xD;
      cardiomyocyte stiffness and hypertrophy. Plasma sodium stiffens vascular endothelium and&#xD;
      reduces NO release. Thus, renal sodium retention may play a pivotal role in the&#xD;
      pathophysiology of HFpEF. Patients with HFrEF indeed have abnormal renal sodium excretion in&#xD;
      response to salt load; however, it remains unclear if patients with HFpEF also have an&#xD;
      impaired renal sodium excretion in response to a salt load, volume expansion or diuretics.&#xD;
&#xD;
      Since (as noted above) renal sodium retention may play an important role in the&#xD;
      pathophysiology of HFpEF, it may be critically important to characterize renal sodium&#xD;
      handling in patients with clinical HFpEF in response to salt loading, intravascular expansion&#xD;
      and diuretic challenge. Impaired sodium excretion has been previously demonstrated in&#xD;
      response to volume expansion in pre-clinical systolic and diastolic dysfunction, but not in&#xD;
      patients with clinical HFpEF. Further, it is of note that this impairment in renal sodium&#xD;
      excretion is rescued by exogenous B-type natriuretic peptide (BNP), which is a natriuretic&#xD;
      peptide that is increased in most patients with HFpEF. It is possible, although not reported,&#xD;
      that baseline BNP [which is commonly assessed by N-terminal prohormone of BNP (NT-proBNP)]&#xD;
      levels affect renal sodium handling in HFpEF patients in response to salt and volume load, or&#xD;
      diuretic challenge. It is also unknown if baseline kidney function, measured by estimated&#xD;
      glomerular filtration rate (eGFR), affects natriuresis in patients with HFpEF after salt&#xD;
      loading or diuretic challenge. Renal tubular function may also have important effects on salt&#xD;
      retention in HF patients.&#xD;
&#xD;
      Characterization of the natriuretic response to intravascular salt and volume load and&#xD;
      diuretic challenge, and of tubular function, in patients with HFpEF will provide insight into&#xD;
      the pathophysiology of HFpEF, and may help in the development of novel strategies to target&#xD;
      renal sodium handling in patients with HFpEF.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 6, 2019</start_date>
  <completion_date type="Actual">February 20, 2020</completion_date>
  <primary_completion_date type="Actual">February 20, 2020</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Urinary Sodium Excretion</measure>
    <time_frame>5 Hours</time_frame>
    <description>Amount of sodium excretion following saline loading and diuretic challenge will be compared between HFpEF patients and controls</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine Volume</measure>
    <time_frame>5 Hours</time_frame>
    <description>Volume of urine collected following saline loading and diuretic challenge will be compared between HFpEF patients and controls</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in NT-proBNP</measure>
    <time_frame>5 Hours</time_frame>
    <description>Average change in NT-proBNP values before and after saline loading and diuretic challenge will be compared between HFpEF patients and controls</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Aldosterone</measure>
    <time_frame>5 Hours</time_frame>
    <description>Serum Aldosterone levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Renin Activity</measure>
    <time_frame>5 Hours</time_frame>
    <description>Plasma renin activity levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Nor-epinephrine</measure>
    <time_frame>5 Hours</time_frame>
    <description>Plasma nor-epinephrine levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Urinary Exosomes</measure>
    <time_frame>5 Hours</time_frame>
    <description>Sodium transporters in Urinary exosomes will be characterized and compared between HFpEF patients and controls</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Heart Failure With Preserved Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>Saline Loading and Diuretic Challenge</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects receive intravenous infusion of 0.9% Sodium Chloride, followed by diuretic challenge with bolus injection of Furosemide 40 mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>0.9% Sodium Chloride</intervention_name>
    <description>Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes</description>
    <arm_group_label>Saline Loading and Diuretic Challenge</arm_group_label>
    <other_name>normal saline</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Furosemide 40 mg</intervention_name>
    <description>Bolus intravenous injection of 40 mg furosemide</description>
    <arm_group_label>Saline Loading and Diuretic Challenge</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  History of chronic (&gt; 6 months) heart failure with current New York Heart Association&#xD;
             II-III symptoms&#xD;
&#xD;
          -  Left ventricular ejection fraction &gt; 50% on a clinically indicated echocardiogram&#xD;
             obtained within last 12 months&#xD;
&#xD;
          -  Clinical compensated heart failure&#xD;
&#xD;
          -  On constant medical therapy for heart failure; without changes in heart failure&#xD;
             medication regimen (including diuretics) for previous 14 days and not expected to&#xD;
             change in the next 2 days&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to comply with protocol or procedures&#xD;
&#xD;
          -  Uncontrolled severe hypertension: systolic blood pressure &gt; 160 mmHg&#xD;
&#xD;
          -  Significant renal impairment as defined by estimated glomerular filtration rate &lt;&#xD;
             30ml/min/1.73m^2 determined by Chronic Kidney Disease - Epidemiology Collaboration&#xD;
             equation&#xD;
&#xD;
          -  Significant proteinuria (&gt; 0.5 g protein/daily protein or equivalent)&#xD;
&#xD;
          -  Body Mass Index &gt; 40 kg/m^2&#xD;
&#xD;
          -  Acute coronary syndrome within last 4 weeks&#xD;
&#xD;
          -  Coronary revascularization procedures (percutaneous coronary intervention or cardiac&#xD;
             artery bypass graft) or valve surgery within 30 days of screening&#xD;
&#xD;
          -  Cardiac resynchronization therapy, with or without implantable cardioverter&#xD;
             defibrillator within 90 days of screening&#xD;
&#xD;
          -  Clinically relevant cardiac valvular disease&#xD;
&#xD;
          -  Hypertrophic or restrictive cardiomyopathy, constrictive pericarditis, active&#xD;
             myocarditis, active endocarditis, or complex congenital heart disease&#xD;
&#xD;
          -  Cirrhosis of the liver&#xD;
&#xD;
          -  History of known hydronephrosis&#xD;
&#xD;
          -  History of adrenal insufficiency&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adhish Agarwal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Utah</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>28460827</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28492288</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>16855265</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24621794</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21856484</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>12413374</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23684677</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>26861140</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23040569</PMID>
  </reference>
  <reference>
    <citation>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. Erratum In: Circulation. 2020 May 12;141(19):e809.</citation>
    <PMID>12578874</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19324256</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>15665834</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>27742422</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>26682792</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21576513</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>29414252</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28656481</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24980489</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17911245</PMID>
  </reference>
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    <citation>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.</citation>
    <PMID>9260976</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28545850</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22051332</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23313577</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20659949</PMID>
  </reference>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>February 8, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>April 14, 2021</last_update_submitted>
  <last_update_submitted_qc>April 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Utah</investigator_affiliation>
    <investigator_full_name>Adhish Agarwal</investigator_full_name>
    <investigator_title>Associate Professor, Nephrology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Furosemide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03837470
org study id: IRB_00112270
nct id: NCT03837470
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Urinary Sodium Excretion
time frame: 5 Hours
description: Amount of sodium excretion following saline loading and diuretic challenge will be compared between HFpEF patients and controls
measure: Urine Volume
time frame: 5 Hours
description: Volume of urine collected following saline loading and diuretic challenge will be compared between HFpEF patients and controls
measure: Change in NT-proBNP
time frame: 5 Hours
description: Average change in NT-proBNP values before and after saline loading and diuretic challenge will be compared between HFpEF patients and controls
measure: Serum Aldosterone
time frame: 5 Hours
description: Serum Aldosterone levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls
measure: Plasma Renin Activity
time frame: 5 Hours
description: Plasma renin activity levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls
measure: Plasma Nor-epinephrine
time frame: 5 Hours
description: Plasma nor-epinephrine levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls
measure: Urinary Exosomes
time frame: 5 Hours
description: Sodium transporters in Urinary exosomes will be characterized and compared between HFpEF patients and controls
arm group label: Saline Loading and Diuretic Challenge
arm group type: Experimental
description: Subjects receive intravenous infusion of 0.9% Sodium Chloride, followed by diuretic challenge with bolus injection of Furosemide 40 mg
intervention type: Drug
intervention name: 0.9% Sodium Chloride
description: Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes
arm group label: Saline Loading and Diuretic Challenge
other name: normal saline
intervention type: Drug
intervention name: Furosemide 40 mg
description: Bolus intravenous injection of 40 mg furosemide
arm group label: Saline Loading and Diuretic Challenge
criteria: 
gender: All
minimum age: 21 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Adhish Agarwal, MD
role: Principal Investigator
affiliation: University of Utah
facility: 
country: United States
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responsible party type: Sponsor-Investigator
investigator affiliation: University of Utah
investigator full name: Adhish Agarwal
investigator title: Associate Professor, Nephrology
mesh term: Heart Failure
mesh term: Furosemide
sharing ipd: No