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Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a

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ClinicalTrials.gov Identifier: NCT02772068
Recruitment Status : Withdrawn (The grant for this project wasn't funded, so there has been no enrollment. We are still hopeful that the project will go forward some day, but not now.)
First Posted : May 13, 2016
Last Update Posted : September 13, 2019
Sponsor:
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Study Description
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Brief Summary:
Heart failure with preserved ejection fraction or HFpEF, represents nearly 50% of all heart failure cases and is particularly common in the elderly. The disease has no current treatment options. Symptoms typically occur during exertion or exercise and is likely the result of increased cardiac and pulmonary congestion as a result of impaired diastolic function. Istaroxime is a novel activator of SERCA2a, an important regulator of calcium uptake within the myocyte. We will test the hypothesis that Istaroxime will improve diastolic function during exercise in HFpEF patients which in turn will reduce cardiac and pulmonary congestion.

Condition or disease Intervention/treatment Phase
Heart Failure, Congestive Drug: Istaroxime Other: Exercise Early Phase 1

Detailed Description:

About half of all elderly patients with a diagnosis of congestive heart failure have apparently normal systolic function, so called "heart failure with a preserved ejection fraction" or HFpEF. To date, no effective therapy for HFpEF has been found, in part because of failure to discern key pathophysiologic pathways.

An extensive amount of pre-clinical work has identified that altered sarcoplasmic reticulum (SR) Ca2+ uptake, storage, and release play a major role in the changes in cardiac relaxation associated with aging, especially regarding sequestration of Ca++ by the sarcoplasmic reticular Ca++-ATPase (SERCA2a), which causes cardiac muscle relaxation by reducing cytosolic Ca++. Istaroxime is a relatively new drug that augments lusitropic function by upregulating SERCA2a activity in the heart.

Because of the clear importance of slowed relaxation in HFpEF, and the evidence that depressed SERCA2a activity contributes to the slowed relaxation with aging, the proposed study may be establish the "impairment of SERCA2a" hypothesis as a mechanism of impaired relaxation in HFpEF subjects.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Hemodynamic Response to Exercise in Heart Failure With Preserved Ejection Fraction (HFpEF) Patients After Upregulation of SERCA2a
Study Start Date : September 2015
Actual Primary Completion Date : December 1, 2018
Actual Study Completion Date : December 1, 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Healthy Senior Control
Fifteen healthy senior subjects will perform light exercise at a fixed heart rate of 100 beats per minute. Subjects will then be given either placebo infusion (normal saline) or Istaroxime infusion for one hour. Subjects will be blinded to which infusion they are receiving. Subjects will then repeat light exercise at a fixed heart rate of 100 beats per minute. Primary outcome is changes in cardiac filling pressures during exercise.
 Drug: Istaroxime
Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.
Other Name: exercise

Other: Exercise
Experimental: Heart failure patients
Fifteen HFpEF subjects will perform light exercise at a fixed heart rate of 100 beats per minute. Subjects will then be given either placebo infusion (normal saline) or Istaroxime infusion for one hour. Subjects will be blinded to which infusion they are receiving. Subjects will then repeat light exercise at a fixed heart rate of 100 beats per minute. Primary outcome is changes in cardiac filling pressures during exercise.
 Drug: Istaroxime
Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.
Other Name: exercise

Other: Exercise


Outcome Measures
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Primary Outcome Measures :
  1. Change in cardiac filling pressures (pulmonary capillary wedge pressure) during exercise with Istaroxime [ Time Frame: Immediate; 90 minutes after infusion ]
    Change in cardiac filling pressures (pulmonary capillary wedge pressure) during exercise with Istaroxime


Secondary Outcome Measures :
  1. Change in cardiac relaxation time (isovolumic relaxation time) during exercise with Istaroxime [ Time Frame: 90 minutes ]
    Change in cardiac relaxation time (isovolumic relaxation time) during exercise


Eligibility Criteria
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Ages Eligible for Study:   60 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Healthy Senior Controls

Inclusion Criteria:

  • age > 60 years

Exclusion Criteria:

  • Coronary Ischemia
  • No chronic medical problems
  • BMI > 30 kg/m2

HFpEF Subjects

Inclusion Criteria:

  • age > 60 years
  • signs and symptoms of heart failure
  • ejection fraction > 50%
  • objective evidence of diastolic dysfunction

Exclusion Criteria:

  • Coronary Ischemia
  • Chronic Kidney Disease, stage 4 or greater
  • Persistent atrial fibrillation
  • Severe valvular disease
  • BMI > 40 kg/m2
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02772068


Locations
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United States, Texas
The Institute for Exercise and Environmental Medicine
Dallas, Texas, United States, 75231
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Investigators
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Principal Investigator: Benjamin D Levine, MD UT Southwestern
More Information
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Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT02772068    
Other Study ID Numbers: STU 042013-039
First Posted: May 13, 2016    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases