Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a

Hemodynamic Response to Exercise in Heart Failure With Preserved Ejection Fraction (HFpEF) Patients After Upregulation of SERCA2a

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure, Congestive
• Intervention / Treatment: Other: Exercise; Drug: Istaroxime

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 Type: Interventional
• Enrollment (Actual): 26
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75231
      • The Institute for Exercise and Environmental Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 > 45 kg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Other: Exercise; Drug: Istaroxime; Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.; Other Names: 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.	Other: Exercise; Drug: Istaroxime; Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.; Other Names: exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cardiac filling pressures (pulmonary capillary wedge pressure) during exercise with Istaroxime	Change in cardiac filling pressures (pulmonary capillary wedge pressure) during exercise with Istaroxime	Immediate; 90 minutes after infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cardiac relaxation time (isovolumic relaxation time) during exercise with Istaroxime	Change in cardiac relaxation time (isovolumic relaxation time) during exercise	90 minutes

Collaborators and Investigators

• Sponsor: Benjamin Levine
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Benjamin D Levine, MD, UT Southwestern

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 15, 2015
• Primary Completion (ACTUAL): December 1, 2018
• Study Completion (ACTUAL): December 1, 2018

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: May 12, 2016
• First Posted (ESTIMATE): May 13, 2016

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 22, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: STU 042013-039; R01AG017479 (NIH)