Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a

Benjamin Levine

Status and phase: Completed; Early Phase 1

Conditions: Heart Failure, Congestive

Treatments: Drug: Istaroxime; Other: Exercise

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02772068

STU 042013-039

R01AG017479 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 26 patients

Sex: All

Ages: 60 to 85 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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 > 45 kg/m2

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

---

26 participants in 2 patient groups

Healthy Senior Control

Active Comparator group

Description:

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.

Treatment:

Other: Exercise

Drug: Istaroxime

Heart failure patients

Experimental group

Description:

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.

Treatment:

Other: Exercise

Drug: Istaroxime