Congestive Heart Failure
Conditions
Keywords
metabolism, congestive heart failure, allopurinol, Adenosine triphosphate (ATP)
Brief summary
This study tests the hypothesis that allopurinol, a xanthine oxidase inhibitor, improves heart metabolism in patients with heart failure.
Detailed description
Xanthine oxidase have been reported to improve mechano-energetic coupling in failing hearts. The investigators developed a means to directly measure creatine kinase flux, the major energy reserve of the heart, in the human heart exploiting new magnetic resonance technologies. The investigators propose to study 10 healthy subjects and up to 25 with heart failure (dilated cardiomyopathy) before and after a single 300mg IV infusion of allopurinol.
Interventions
DRUGAllopurinol
intravenous infusion of allopurinol (300mg)
DRUGPlacebo
intravenous infusion of 50 ml dose of 5% dextrose
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 years * The patient is willing and able to provide informed consent * Clinical diagnosis of chronic heart failure * Ejection fraction (EF) \< 40% by echocardiography, nuclear multigated acquisition (MUGA) or cath ventriculography * No significant coronary disease at cardiac catheterization * New York Heart Association (NYHA) Class I-IV symptoms * Clinical stabilization for two weeks if following recent congestive heart failure (CHF) decompensation.
Exclusion criteria
* Metallic implant prohibiting magnetic resonance (MR) evaluation * Inability to lie flat for MR study * Administration of additional investigational drugs * Calculated creatinine clearance \< 50 mL/min * Allergy to allopurinol * Current gout flare * Currently taking oral allopurinol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Creatine Kinase (CK) Flux Pre Intravenous Allopurinol Infusion | Onset of imaging acquisition. | Magnetic resonance spectroscopy (MRS) Measurement of Myocardial CK Flux Pre Intravenous Allopurinol Infusion |
| Myocardial CK Flux Post Intravenous Allopurinol Infusion. | acute (within 15 minutes of single infusion) | The mean rate of adenosine triphosphate (ATP) flux through the creatine kinase reaction in the heart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac PCr/ATP Pre Intravenous Infusion | Onset of image acquisition. | The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless. |
| Cardiac PCr/ATP Post Intravenous Infusion | acute (within 15 minutes of single infusion) | The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless. |
Countries
United States
Participant flow
Recruitment details
Participants with Non-Ischemic Cardiomyopathy were recruited as approved by the Johns Hopkins Institutional Review Board for Human Investigation.
Pre-assignment details
The study drug allocation was randomized in a 4:1 fashion by the research pharmacy. Participants were randomized to Placebo only for the purposes of blinding; Adverse Events were collected for the Placebo arm.
Participants by arm
| Arm | Count |
|---|---|
| Intravenous Allopurinol We randomized patients with nonischemic cardiomyopathy in a double-blind fashion to allopurinol (300 mg intravenously) or placebo infusion, 4-to-1, the latter for purposes of blinding only. The myocardial concentrations of ATP and creatine phosphate (PCr) and the rate of adenosine triphosphate (ATP) synthesis through CK (CK flux) were determined by 31-Phosphorus (31P) magnetic resonance spectroscopy. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Intravenous Allopurinol |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 47.8 years STANDARD_DEVIATION 12.9 |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 3 |
| serious Total, serious adverse events | 0 / 13 | 0 / 3 |
Outcome results
Primary
Myocardial CK Flux Post Intravenous Allopurinol Infusion.
The mean rate of adenosine triphosphate (ATP) flux through the creatine kinase reaction in the heart.
Time frame: acute (within 15 minutes of single infusion)
Population: Data were analyzed for all participants who completed the MRS per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Myocardial CK Flux Post Intravenous Allopurinol Infusion. | 2.87 umol/g/sec | Standard Deviation 1.82 |
p-value: <0.007Two-sided paired t tests
Primary
Myocardial Creatine Kinase (CK) Flux Pre Intravenous Allopurinol Infusion
Magnetic resonance spectroscopy (MRS) Measurement of Myocardial CK Flux Pre Intravenous Allopurinol Infusion
Time frame: Onset of imaging acquisition.
Population: Data were analyzed for all participants who completed the MRS per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Myocardial Creatine Kinase (CK) Flux Pre Intravenous Allopurinol Infusion | 2.07 umol/g/sec | Standard Deviation 1.27 |
Secondary
Cardiac PCr/ATP Post Intravenous Infusion
The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless.
Time frame: acute (within 15 minutes of single infusion)
Population: Data were analyzed for all participants who completed the MRS per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Cardiac PCr/ATP Post Intravenous Infusion | 1.75 ratio | Standard Deviation 0.59 |
p-value: <0.02Two-sided paired t tests
Secondary
Cardiac PCr/ATP Pre Intravenous Infusion
The mean ratio of creatine phosphate (PCr) to ATP in the heart. This measure, as a ratio, is unitless.
Time frame: Onset of image acquisition.
Population: Data were analyzed for all participants who completed the MRS per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Cardiac PCr/ATP Pre Intravenous Infusion | 1.58 ratio | Standard Deviation 0.41 |