Improving Right Ventricular Function in Young Adults Born Preterm

Study Overview
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Brief Summary
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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
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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.

Official Title
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Improving Right Ventricular Function in Young Adults Born Preterm: A Pilot Study

Conditions
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Infant,Premature

Intervention / Treatment
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* Procedure: Pulmonary Function Testing
* Procedure: Electrocardiogram
* Procedure: Cardiac Magnetic Resonance Imaging
* Drug: Metoprolol
* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Male or female aged 18-35 History of preterm birth (either a or b): Participant in the Newborn Lung Project (birth year 1988-1991, birth weight <1500 g) Non-NLP participant, with birth weight <1500 g and gestational age 32 weeks or less, verified by medical records Exclusion Criteria: Pregnant or lactating Use of prescribed medications that would interfere with study medications Sildenafil: Use of phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil), nitrates, soluble guanylate cyclase inhibitor (riociguat) within 48 hours of study visit Metoprolol: Use of nodal blocking agents including beta blockers, non-dihydropyridine calcium channel blockers (i.e. diltiazem), and anti-arrhythmics (i.e. amiodarone) Presence of known comorbidities for which these therapeutic interventions would be contraindicated: Moderate to severe heart failure Severe bradycardia (heart rate <45), or second or third-degree heart block Systolic blood pressure <90 mmHg or >190 mmHg Angina Severe peripheral arterial circulatory disorders History of severe bronchospasm Presence of any implanted device incompatible with CMR imaging Known allergic or hypersensitivity reaction to components of the study medications Any other reason for which the investigator deems a subject unsafe or inappropriate for study participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil followed by Metoprolol<br>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 next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram. | Procedure: Pulmonary Function Testing<br>* Subjects will undergo spirometry, Plethysmography, and diffusion capacity.<br>Procedure: Electrocardiogram<br>* Subjects will undergo an electrocardiogram to ensure sinus rhythm<br>Procedure: Cardiac Magnetic Resonance Imaging<br>* Subjects will undergo positron magnetic resonance imaging to detect images of the heart<br>Drug: Metoprolol<br>* 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.<br>* Other names: Metolar XR;Drug: Sildenafil<br>* Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally)<br>* Other names: Revatio;|
| Experimental: Metoprolol followed by Sildenafil<br>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 metoprolol in between imaging scans at one visit, and will receive intravenous sildenafil in between scans at next visit. There will be a minimum period of 12 hours between drug interventions to ensure adequate drug wash-out. Subjects will also undergo pulmonary function testing and electrocardiogram. | Procedure: Pulmonary Function Testing<br>* Subjects will undergo spirometry, Plethysmography, and diffusion capacity.<br>Procedure: Electrocardiogram<br>* Subjects will undergo an electrocardiogram to ensure sinus rhythm<br>Procedure: Cardiac Magnetic Resonance Imaging<br>* Subjects will undergo positron magnetic resonance imaging to detect images of the heart<br>Drug: Metoprolol<br>* 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.<br>* Other names: Metolar XR;Drug: Sildenafil<br>* Subjects will receive a 50 milligram tablet of sildenafil (to be taken orally)<br>* Other names: Revatio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 2 hours | 
| 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. | up to 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 2 hours | 
| Right Ventricular Ejection Fraction Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Right Ventricular Stroke Volume Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Right Ventricular Systolic Volume Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Right Ventricular Diastolic Volume Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Left Ventricular Ejection Fraction Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Left Ventricular Stroke Volume Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Left Ventricular Systolic Volume Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| Left Ventricular Diastolic Volume Pre and Post Metoprolol | Participants will receive intravenous metoprolol in between scans. | up to 2 hours | 
| 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. | up to 2 hours | 
| 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. | up to 2 hours | 
| Right Ventricular Stroke Volume Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 
| Right Ventricular Systolic Volume Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 
| Right Ventricular Diastolic Volume Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 
| Left Ventricular Ejection Fraction Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 
| Left Ventricular Stroke Volume Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 
| Left Ventricular Systolic Volume Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 
| Left Ventricular Diastolic Volume Pre and Post Sildenafil | Participants will be given sildenafil in between imaging scans. | up to 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, premature adults, premature, premature cardiac function, sildenafil, metoprolol, CMR