Marfan Syndrome
Conditions
Keywords
Marfan syndrome, Losartan, Atenolol, Diastolic Function, Aortic Stiffness
Brief summary
Marfan syndrome is an inherited connective tissue disorder with morbidity and mortality from aortic dilation and dissection. The degree of aortic dilation and response to beta-blockade (standard of care) vary in adults with Marfan syndrome. However, aortic stiffness is often present, and can be a predictor of aortic dilation and cardiovascular complications. In addition, adults with Marfan syndrome develop left ventricular diastolic dysfunction, which can progress to heart failure. Aortic stiffness and diastolic dysfunction are important and logical therapeutic targets in adults with Marfan syndrome. TGF-beta mediates disease pathogenesis in Marfan syndrome and contributes to aortic stiffness. The angiotensin receptor blocker, losartan, inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. Losartan also decreases aortic stiffness and improves diastolic function in hypertension, renal disease and hypertrophic cardiomyopathy. This trial is a randomized, double-blind trial of 50 adults with Marfan syndrome, treated with 6 months of atenolol vs. losartan. Arterial tonometry for aortic stiffness and echocardiography for diastolic function will be performed at the beginning and end of treatment. A blood draw for serum markers of extracellular matrix turnover and inflammation will also be performed at 0 and 6 months. We plan to determine whether losartan decreases aortic stiffness and left ventricular diastolic dysfunction significantly more than atenolol.
Detailed description
Please See Summary.
Interventions
DRUGAtenolol
Atenolol 50mg PO QD
DRUGLosartan
Losartan 100mg PO QD
Sponsors
Boston Children's Hospital
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than 25 years * Clinical Marfan Syndrome
Exclusion criteria
* Previous aortic or cardiac surgery * Pregnancy * Renal Insufficiency * Medication intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aortic Biophysical Properties - Pulse Wave Velocity | Baseline and 6 months | Aortic stiffness was assessed using applanation tonometry (SphygmoCor®, AtCor Medical, West Ryde, NSW, Sydney, Australia) to measure carotid to femoral artery pulse wave velocity (PWV). With the patient lying supine in a quiet environment, a handheld micromanometer-tipped probe was applied to the skin surface over the carotid and femoral arteries, compressing the vessel wall so that transmural forces within the vessel wall were perpendicular to the arterial surface. The distance from the sternal notch to the sites of carotid and femoral pulse acquisition were measured and inputted into the device to represent the relative distance from the carotid to femoral artery. The calculation of distance divided by time of pulse upstroke relative to the upstroke of the QRS on a 3 lead surface EKG was used by the device to calculate velocity. All recorded measurements met the manufacturer's quality control standards integrated into the software package. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diastolic Function - Ejection Fraction | Baseline and 6 months | Two-dimensional echocardiography was performed using a 3.0 MHz transducer (General Electric VIVID 7). Left ventricular and left atrial dimensions were determined in parasternal long axis views. Left ventricular ejection fraction was calculated using the modified Simpsons calculation in the apical two and four chamber views. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subjects Randomized to Atenolol Atenolol: Atenolol 50mg PO QD | 17 |
| Subjects Randomized to Losartan Losartan: Losartan 100mg PO QD | 17 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol Violation | 2 | 1 |
Baseline characteristics
| Characteristic | Subjects Randomized to Atenolol | Subjects Randomized to Losartan | Total |
|---|---|---|---|
| Age, Continuous | 34 years | 36 years | 35 years |
| Ejection Fraction | 60 % STANDARD_DEVIATION 4 | 62 % STANDARD_DEVIATION 6 | 61 % STANDARD_DEVIATION 5 |
| Pulse wave velocity | 7.5 meters/second STANDARD_DEVIATION 1.6 | 7.6 meters/second STANDARD_DEVIATION 2.4 | 7.55 meters/second STANDARD_DEVIATION 2 |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Aortic Biophysical Properties - Pulse Wave Velocity
Aortic stiffness was assessed using applanation tonometry (SphygmoCor®, AtCor Medical, West Ryde, NSW, Sydney, Australia) to measure carotid to femoral artery pulse wave velocity (PWV). With the patient lying supine in a quiet environment, a handheld micromanometer-tipped probe was applied to the skin surface over the carotid and femoral arteries, compressing the vessel wall so that transmural forces within the vessel wall were perpendicular to the arterial surface. The distance from the sternal notch to the sites of carotid and femoral pulse acquisition were measured and inputted into the device to represent the relative distance from the carotid to femoral artery. The calculation of distance divided by time of pulse upstroke relative to the upstroke of the QRS on a 3 lead surface EKG was used by the device to calculate velocity. All recorded measurements met the manufacturer's quality control standards integrated into the software package.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects Randomized to Atenolol | Aortic Biophysical Properties - Pulse Wave Velocity | -1.15 change in meters/second | Standard Deviation 1.68 |
| Subjects Randomized to Losartan | Aortic Biophysical Properties - Pulse Wave Velocity | -0.22 change in meters/second | Standard Deviation 0.59 |
Secondary
Diastolic Function - Ejection Fraction
Two-dimensional echocardiography was performed using a 3.0 MHz transducer (General Electric VIVID 7). Left ventricular and left atrial dimensions were determined in parasternal long axis views. Left ventricular ejection fraction was calculated using the modified Simpsons calculation in the apical two and four chamber views.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Subjects Randomized to Atenolol | Diastolic Function - Ejection Fraction | 1.31 Change in % ejection fraction | Standard Deviation 4.07 |
| Subjects Randomized to Losartan | Diastolic Function - Ejection Fraction | 1.57 Change in % ejection fraction | Standard Deviation 8.29 |