Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a

NCT ID: NCT02772068

Last Updated: 2022-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-15
• Study Completion Date: 2018-12-01

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.

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.

Conditions

Heart Failure, Congestive

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Istaroxime

Intervention Type: DRUG

Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.

Exercise

Intervention Type: OTHER

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.

Group Type: EXPERIMENTAL

Istaroxime

Intervention Type: DRUG

Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.

Exercise

Intervention Type: OTHER

Interventions

Istaroxime

Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.

Intervention Type: DRUG

Exercise

Intervention Type: OTHER

Other Intervention Names

exercise

Eligibility Criteria

Inclusion Criteria

• age > 60 years

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

Exclusion Criteria

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

HFpEF Subjects

• Coronary Ischemia
• Chronic Kidney Disease, stage 4 or greater
• Persistent atrial fibrillation
• Severe valvular disease
• BMI > 45 kg/m2

• Minimum Eligible Age: 60 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Benjamin Levine

OTHER

Sponsor Role: lead

Responsible Party

Benjamin Levine

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Benjamin D Levine, MD

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern

Locations

The Institute for Exercise and Environmental Medicine

Dallas, Texas, United States

Countries

United States

References

Sarma S, MacNamara JP, Hieda M, Howden EJ, Lawley JS, Livingston S, Samels M, Levine BD. SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2023 Jul;11(7):760-771. doi: 10.1016/j.jchf.2023.02.006. Epub 2023 Apr 19.

Reference Type: DERIVED

PMID: 37086245 (View on PubMed)

Other Identifiers

R01AG017479

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU 042013-039

Identifier Type: -

Identifier Source: org_study_id