Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a

Sponsor

Benjamin Levine (Other)

Overall Status

Completed

CT.gov ID

NCT02772068

Collaborator

National Institute on Aging (NIA) (NIH)

Enrollment

Location

Arms

38.5

Actual Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Actual Enrollment :

26 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Two separate groups of subjects (senior controls and patients with HFpEF) receiving istaroximeTwo separate groups of subjects (senior controls and patients with HFpEF) receiving istaroxime

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

Actual Study Start Date :

Sep 15, 2015

Actual Primary Completion Date :

Dec 1, 2018

Actual Study Completion Date :

Dec 1, 2018

Arms and Interventions

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 Names: 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 Names: exercise Other: Exercise

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 Names:

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 Names:

exercise

Other: Exercise

Outcome Measures

Primary Outcome Measures

Change in cardiac filling pressures (pulmonary capillary wedge pressure) during exercise with Istaroxime [Immediate; 90 minutes after infusion]
Change in cardiac filling pressures (pulmonary capillary wedge pressure) during exercise with Istaroxime

Secondary Outcome Measures

Change in cardiac relaxation time (isovolumic relaxation time) during exercise with Istaroxime [90 minutes]
Change in cardiac relaxation time (isovolumic relaxation time) during exercise

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Institute for Exercise and Environmental Medicine	Dallas	Texas	United States	75231

Sponsors and Collaborators

Benjamin Levine
National Institute on Aging (NIA)

Investigators

Principal Investigator: Benjamin D Levine, MD, UT Southwestern

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Benjamin Levine, Professor, University of Texas Southwestern Medical Center

ClinicalTrials.gov Identifier:

NCT02772068

Other Study ID Numbers:

STU 042013-039
R01AG017479

First Posted:

May 13, 2016

Last Update Posted:

Jun 29, 2022

Last Verified:

Jun 1, 2022

Additional relevant MeSH terms:

Heart Failure

Study Results

No Results Posted as of Jun 29, 2022