Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Heart Failure, Congestive

Intervention / Treatment
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* Drug: Istaroxime
* Other: Exercise


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two separate groups of subjects (senior controls and patients with HFpEF) receiving istaroxime
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Healthy Senior Control<br>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<br>* Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.<br>* Other names: exercise;Other: Exercise<br> <br> |
| Experimental: Heart failure patients<br>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<br>* Subjects will be given Istaroxime, a novel SERCA2a activator one hour prior and during exercise.<br>* Other names: exercise;Other: Exercise<br> <br> |

What is the study measuring?
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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 |