Infant,Premature
Conditions
Keywords
premature adults, premature, premature cardiac function, MRI, sildenafil, metoprolol, CMR
Brief summary
The purpose of this research is to evaluate the short-term effects of sildenafil and metoprolol on heart function in young adults born premature.
Detailed description
The purpose of this study is to evaluate the short-term therapeutic effects of sildenafil and metoprolol on right ventricular function in young adults born premature using novel 4-Dimensional flow Cardiac Magnetic Resonance Imaging.
Interventions
PROCEDUREPulmonary Function Testing
Subjects will undergo spirometry, Plethysmography, and diffusion capacity.
PROCEDUREElectrocardiogram
Subjects will undergo an electrocardiogram to ensure sinus rhythm
PROCEDURECardiac Magnetic Resonance Imaging
Subjects will undergo positron magnetic resonance imaging to detect images of the heart
DRUGMetoprolol
Subjects will receive intravenous metoprolol. Dose titrated 1-5 mg every 2 minutes to achieve goal heart rate of 55-65 beats per minute, or for subjects with a resting heart rate already at goal, titrated to achieve a 10-15% reduction in heart rate.
DRUGSildenafil
Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally)
Sponsors
National Center for Advancing Translational Sciences (NCATS)
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at a separate visit. These visits can occur in either order. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out.
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form 2. Male or female aged 18-35 3. History of preterm birth (either a or b): 1. Participant in the Newborn Lung Project (birth year 1988-1991, birth weight \<1500 g) 2. Non-NLP participant, with birth weight \<1500 g and gestational age 32 weeks or less, verified by medical records
Exclusion criteria
1. Pregnant or lactating 2. Use of prescribed medications that would interfere with study medications 1. Sildenafil: Use of phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil), nitrates, soluble guanylate cyclase inhibitor (riociguat) within 48 hours of study visit 2. Metoprolol: Use of nodal blocking agents including beta blockers, non-dihydropyridine calcium channel blockers (i.e. diltiazem), and anti-arrhythmics (i.e. amiodarone) 3. Presence of known comorbidities for which these therapeutic interventions would be contraindicated: 1. Moderate to severe heart failure 2. Severe bradycardia (heart rate \<45), or second or third-degree heart block 3. Systolic blood pressure \<90 mmHg or \>190 mmHg 4. Angina 5. Severe peripheral arterial circulatory disorders 6. History of severe bronchospasm 4. Presence of any implanted device incompatible with CMR imaging 5. Known allergic or hypersensitivity reaction to components of the study medications 6. Any other reason for which the investigator deems a subject unsafe or inappropriate for study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Right Ventricular Energetic Efficiency Pre and Post Metoprolol | up to 2 hours | To characterize energy efficiency, the total Kinetic Energy across the cardiac cycle is normalized to right ventricular end-diastolic volume and left ventricular end-diastolic volume, respectively. Analysis will be completed in blinded fashion. Two imaging scans will be done - one pre and one post Metoprolol intervention. Total time from Pre-intervention scan till post intervention scan may take up to 2 hours. |
| Right Ventricular Energetic Efficiency Pre and Post Sildenafil | up to 2 hours | To characterize energy efficiency, the total Kinetic Energy across the cardiac cycle is normalized to right ventricular end-diastolic volume and left ventricular end-diastolic volume, respectively. Analysis will be completed in blinded fashion. Two imaging scans will be done - one pre and one post Sildenafil intervention. Total time from Pre-intervention scan till post intervention scan may take up to 2 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Right Ventricular Stroke Volume Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Right Ventricular Systolic Volume Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Right Ventricular Diastolic Volume Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Left Ventricular Ejection Fraction Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Left Ventricular Stroke Volume Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Left Ventricular Systolic Volume Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Left Ventricular Diastolic Volume Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
| Left Ventricular Energetic Efficiency Pre and Post Sildenafil | up to 2 hours | Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will be given sildenafil in between imaging scans. |
| Left Ventricular Energetic Efficiency Pre and Post Metoprolol | up to 2 hours | Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will receive intravenous metoprolol in between scans. |
| Right Ventricular Stroke Volume Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Right Ventricular Systolic Volume Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Right Ventricular Diastolic Volume Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Left Ventricular Ejection Fraction Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Left Ventricular Stroke Volume Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Left Ventricular Systolic Volume Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Left Ventricular Diastolic Volume Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. |
| Right Ventricular Ejection Fraction Pre and Post Sildenafil | up to 2 hours | Participants will be given sildenafil in between imaging scans. The term ejection fraction refers to the percentage of blood that's pumped out of a filled ventricle with each heartbeat. |
| Right Ventricular Ejection Fraction Pre and Post Metoprolol | up to 2 hours | Participants will receive intravenous metoprolol in between scans. |
Countries
United States
Participant flow
Pre-assignment details
Due to COVID shut down, 1 participant was excluded from the study before assignment to groups
Participants by arm
| Arm | Count |
|---|---|
| Young Adults Born Premature Young adults born premature, recruited either from the National Lung Project Cohort or the general public, will undergo Cardiac Magnetic Resonance Imaging before and after medication administration. This will occur twice, on two separate visits. Subjects will be given sildenafil in between imaging scans at one visit, and will receive intravenous metoprolol in between scans at a separate visit. These visits can occur in either order. Subjects will also undergo pulmonary function testing and electrocardiogram.
Pulmonary Function Testing: Subjects will undergo spirometry, Plethysmography, and diffusion capacity.
Electrocardiogram: Subjects will undergo an electrocardiogram to ensure sinus rhythm Cardiac Magnetic Resonance Imaging: Subjects will undergo positron magnetic resonance imaging to detect images of the heart Metoprolol: Subjects will receive intravenous metoprolol Sildenafil: Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally) | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Young Adults Born Premature |
|---|---|
| Age, Continuous | 27.8 Years STANDARD_DEVIATION 3.7 |
| Birth weight (Neonatal Characteristics) | 1116 gram STANDARD_DEVIATION 342 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Gestational age (Neonatal Characteristics) | 28.9 Weeks STANDARD_DEVIATION 2.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 0 / 3 | 0 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 6 |
Outcome results
Primary
Right Ventricular Energetic Efficiency Pre and Post Metoprolol
To characterize energy efficiency, the total Kinetic Energy across the cardiac cycle is normalized to right ventricular end-diastolic volume and left ventricular end-diastolic volume, respectively. Analysis will be completed in blinded fashion. Two imaging scans will be done - one pre and one post Metoprolol intervention. Total time from Pre-intervention scan till post intervention scan may take up to 2 hours.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Energetic Efficiency Pre and Post Metoprolol | Pre Metoprolol | 15.5 µJ/ml | Standard Deviation 2.6 |
| Young Adults Born Premature | Right Ventricular Energetic Efficiency Pre and Post Metoprolol | Post Metoprolol | 12.7 µJ/ml | Standard Deviation 2.5 |
p-value: 0.004Wilcoxon Signed Rank Test
Primary
Right Ventricular Energetic Efficiency Pre and Post Sildenafil
To characterize energy efficiency, the total Kinetic Energy across the cardiac cycle is normalized to right ventricular end-diastolic volume and left ventricular end-diastolic volume, respectively. Analysis will be completed in blinded fashion. Two imaging scans will be done - one pre and one post Sildenafil intervention. Total time from Pre-intervention scan till post intervention scan may take up to 2 hours.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Energetic Efficiency Pre and Post Sildenafil | Pre-Sildenafil | 15.8 µJ/ml | Standard Deviation 3.7 |
| Young Adults Born Premature | Right Ventricular Energetic Efficiency Pre and Post Sildenafil | Post-Sildenafil | 17.9 µJ/ml | Standard Deviation 6.2 |
p-value: 0.13Wilcoxon Signed Rank Test
Secondary
Left Ventricular Diastolic Volume Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Diastolic Volume Pre and Post Metoprolol | Pre-Metoprolol | 72.5 ml/m^2 | Standard Deviation 10.1 |
| Young Adults Born Premature | Left Ventricular Diastolic Volume Pre and Post Metoprolol | Post-Metoprolol | 72.1 ml/m^2 | Standard Deviation 9.7 |
p-value: 0.65Wilcoxon Signed Rank Test
Secondary
Left Ventricular Diastolic Volume Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Diastolic Volume Pre and Post Sildenafil | Pre-Sildenafil | 71.2 ml/m^2 | Standard Deviation 8.8 |
| Young Adults Born Premature | Left Ventricular Diastolic Volume Pre and Post Sildenafil | Post-Sildenafil | 72.2 ml/m^2 | Standard Deviation 8 |
p-value: 0.91Wilcoxon Signed Rank Test
Secondary
Left Ventricular Ejection Fraction Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Ejection Fraction Pre and Post Metoprolol | Pre-Metoprolol | 60 percentage | Standard Deviation 6 |
| Young Adults Born Premature | Left Ventricular Ejection Fraction Pre and Post Metoprolol | Post-Metoprolol | 58 percentage | Standard Deviation 8 |
p-value: 0.3Wilcoxon Signed Rank Test
Secondary
Left Ventricular Ejection Fraction Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Ejection Fraction Pre and Post Sildenafil | Pre-Sildenafil | 60 percentage | Standard Deviation 7 |
| Young Adults Born Premature | Left Ventricular Ejection Fraction Pre and Post Sildenafil | Post-Sildenafil | 63 percentage | Standard Deviation 8 |
p-value: 0.25Wilcoxon Signed Rank Test
Secondary
Left Ventricular Energetic Efficiency Pre and Post Metoprolol
Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Energetic Efficiency Pre and Post Metoprolol | Pre-Metoprolol | 11.6 µJ/ml | Standard Deviation 5 |
| Young Adults Born Premature | Left Ventricular Energetic Efficiency Pre and Post Metoprolol | Post-Metoprolol | 9.5 µJ/ml | Standard Deviation 3.7 |
p-value: 0.004Wilcoxon Signed Rank Test
Secondary
Left Ventricular Energetic Efficiency Pre and Post Sildenafil
Kinetic energy (from 4D flow) normalized to ventricular volume (from MRI). Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Energetic Efficiency Pre and Post Sildenafil | Pre-Sildenafil | 11.1 µJ/ml | Standard Deviation 2.8 |
| Young Adults Born Premature | Left Ventricular Energetic Efficiency Pre and Post Sildenafil | Post-Sildenafil | 12.3 µJ/ml | Standard Deviation 4 |
p-value: 0.25Wilcoxon Signed Rank Test
Secondary
Left Ventricular Stroke Volume Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Stroke Volume Pre and Post Metoprolol | Pre-Metoprolol | 43.7 ml/m^2 | Standard Deviation 7.1 |
| Young Adults Born Premature | Left Ventricular Stroke Volume Pre and Post Metoprolol | Post-Metoprolol | 41.4 ml/m^2 | Standard Deviation 5.6 |
p-value: 0.36Wilcoxon Signed Rank Test
Secondary
Left Ventricular Stroke Volume Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Stroke Volume Pre and Post Sildenafil | Pre-Sildenafil | 43.1 ml/m^2 | Standard Deviation 8.1 |
| Young Adults Born Premature | Left Ventricular Stroke Volume Pre and Post Sildenafil | Post-Sildenafil | 45.7 ml/m^2 | Standard Deviation 9.2 |
p-value: 0.07Wilcoxon Signed Rank Test
Secondary
Left Ventricular Systolic Volume Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Systolic Volume Pre and Post Metoprolol | Pre-Metoprolol | 28.8 ml/m^2 | Standard Deviation 6 |
| Young Adults Born Premature | Left Ventricular Systolic Volume Pre and Post Metoprolol | Post-Metoprolol | 30.6 ml/m^2 | Standard Deviation 8.2 |
p-value: 0.36Wilcoxon Signed Rank Test
Secondary
Left Ventricular Systolic Volume Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Left Ventricular Systolic Volume Pre and Post Sildenafil | Pre-Sildenafil | 28.1 ml/m^2 | Standard Deviation 5.4 |
| Young Adults Born Premature | Left Ventricular Systolic Volume Pre and Post Sildenafil | Post-Sildenafil | 26.6 ml/m^2 | Standard Deviation 5.7 |
p-value: 0.36Wilcoxon Signed Rank Test
Secondary
Right Ventricular Diastolic Volume Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Diastolic Volume Pre and Post Metoprolol | Pre-Metoprolol | 75.2 ml/m^2 | Standard Deviation 9.8 |
| Young Adults Born Premature | Right Ventricular Diastolic Volume Pre and Post Metoprolol | Post-Metoprolol | 74.4 ml/m^2 | Standard Deviation 9.4 |
p-value: 0.82Wilcoxon Signed Rank Test
Secondary
Right Ventricular Diastolic Volume Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Diastolic Volume Pre and Post Sildenafil | Post-Sildenafil | 74.6 ml/m^2 | Standard Deviation 11.3 |
| Young Adults Born Premature | Right Ventricular Diastolic Volume Pre and Post Sildenafil | Pre-Sildenafil | 76.2 ml/m^2 | Standard Deviation 9.1 |
p-value: 0.57Wilcoxon Signed Rank Test
Secondary
Right Ventricular Ejection Fraction Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Ejection Fraction Pre and Post Metoprolol | Pre-Metoprolol | 55 percentage | Standard Deviation 8 |
| Young Adults Born Premature | Right Ventricular Ejection Fraction Pre and Post Metoprolol | Post-Metoprolol | 51 percentage | Standard Deviation 8 |
p-value: 0.1Wilcoxon Signed Rank Test
Secondary
Right Ventricular Ejection Fraction Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans. The term ejection fraction refers to the percentage of blood that's pumped out of a filled ventricle with each heartbeat.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Ejection Fraction Pre and Post Sildenafil | Pre-Sildenafil | 53 percentage | Standard Deviation 7 |
| Young Adults Born Premature | Right Ventricular Ejection Fraction Pre and Post Sildenafil | Post-Sildenafil | 55 percentage | Standard Deviation 10 |
p-value: 0.43Wilcoxon Signed Rank Test
Secondary
Right Ventricular Stroke Volume Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Stroke Volume Pre and Post Metoprolol | Pre-Metoprolol | 41.5 ml/m^2 | Standard Deviation 7.6 |
| Young Adults Born Premature | Right Ventricular Stroke Volume Pre and Post Metoprolol | Post-Metoprolol | 37.7 ml/m^2 | Standard Deviation 5.1 |
p-value: 0.09Wilcoxon Signed Rank Test
Secondary
Right Ventricular Stroke Volume Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Stroke Volume Pre and Post Sildenafil | Pre-Sildenafil | 40.4 ml/m^2 | Standard Deviation 5.3 |
| Young Adults Born Premature | Right Ventricular Stroke Volume Pre and Post Sildenafil | Post-Sildenafil | 41.3 ml/m^2 | Standard Deviation 10.7 |
p-value: 0.66Wilcoxon Signed Rank Test
Secondary
Right Ventricular Systolic Volume Pre and Post Metoprolol
Participants will receive intravenous metoprolol in between scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Systolic Volume Pre and Post Metoprolol | Pre-Metoprolol | 33.7 ml/m^2 | Standard Deviation 7.5 |
| Young Adults Born Premature | Right Ventricular Systolic Volume Pre and Post Metoprolol | Post-Metoprolol | 36.6 ml/m^2 | Standard Deviation 9.3 |
p-value: 0.1Wilcoxon Signed Rank Test
Secondary
Right Ventricular Systolic Volume Pre and Post Sildenafil
Participants will be given sildenafil in between imaging scans.
Time frame: up to 2 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Young Adults Born Premature | Right Ventricular Systolic Volume Pre and Post Sildenafil | Pre-Sildenafil | 35.8 ml/m^2 | Standard Deviation 8.5 |
| Young Adults Born Premature | Right Ventricular Systolic Volume Pre and Post Sildenafil | Post-Sildenafil | 33.3 ml/m^2 | Standard Deviation 7.3 |
p-value: 0.13Wilcoxon Signed Rank Test