Long-term Outcomes and Vascular Evaluation After Coarctation of the Aorta Treatment
Long-term Outcomes and Vascular Evaluation After Coarctation of the Aorta Treatment
Background: Coarctation of the aorta (CoA) can be treated using surgery, balloon angioplasty
 or stent implantation. Although short-term results are excellent with all three treatment
 modalities, long term cardiovascular (CV) morbidity and mortality remain high, likely due to
 persistently abnormal vascular function. The effects of treatment modality on long term
 vascular function remain uncharacterized. The goal of this study is to assess vascular
 function in this patient population for comparison among the treatment modalities. Methods:
 Vascular function in large and small arteries will be prospectively assessed fusing multiple
 non-invasive modalities, and the results will be compared among the three groups of CoA
 patients previously treated using surgery, balloon angioplasty or stent implantation after
 frequency matching for confounding variables. A comprehensive vascular function assessment
 protocol was created to be used in 7 centers. The primary outcome is arterial stiffness
 measured by arterial tonometry. Inclusion and exclusion criteria were carefully established
 after consideration of several potential confounders. Sample size was calculated for the
 primary outcome variable. Conclusions: Treatment modalities for CoA may have distinct impact
 on large and small arterial vascular function. The results of this study will help identify
 the treatment modality that is associated with the most optimal level of vascular function,
 which, in the long term may reduce CV risk.
Study overview. This cross-sectional prospective observational study of patients with CoA
 previously treated using one of three treatment modalities assesses if treatment type is
 associated with differences in vascular function. The three treatment groups will be
 frequency-matched for key confounding variables.

 Study feasibility. The investigators assembled a multi-disciplinary team with proven
 expertise in epidemiology, clinical trial design, congenital heart disease, non-invasive
 imaging, interventional cardiology, vascular function assessment, preventive cardiology and
 statistical analysis. A multicenter design is used to ensure sufficient statistical power in
 evaluating the hypothesis.

 Participating centers and study core laboratories. Patients are recruited at six large
 pediatric cardiac centers from Portugal and USA.

 Screening procedures. The medical records of potentially eligible patients are screened by a
 local study investigator using a pre-specified screening form to ensure that they satisfy our
 selection criteria.

 Overview of the study workflow. Study procedures will occur in a one- or two-day visit. Upon
 arrival for testing, formal consent for participation will be obtained. Assessment of
 arterial stiffness, endothelial function, and blood sampling for biomarkers will be done
 while fasting. Cardiopulmonary stress test will be performed on the same day. CMR and
 ambulatory blood pressure monitoring (ABMP) will be arranged for the same or for the
 following day. When the study tests cannot be completed at the first visit, they will be
 completed within 3 months of the first visit. The study protocol was approved by the
 Institutional Review Board or Institutional Ethics Committee at each participating center,
 and informed consent and assent will be obtained, depending on age, from patients and their
 parents/legal guardians before trial enrollment.

 Recruitment. A review of the patient database at each participating institution will be
 performed to assemble a cohort of patients with CoA who have previously undergone treatment
 with balloon dilation, surgery or stenting. Study data will be collected and managed using
 REDCap electronic data capture tools hosted at Boston Children's Hospital.

 Data collection. A retrospective chart review will be performed to collect demographic and
 clinical data including severity of coarctation, type and details of CoA treatment and
 presence of associated conditions.

 Diagnostic procedures.

 Arterial Stiffness Plan & Rationale:

 Measurements: Carotid-femoral PWV (cfPWV) will be measured using applanation tonometry.
 Segmental PWV is measured using CMR. Segmental measures of arterial distensibility will be
 measured using CMR. Other parameters that describe arterial stiffness reflect the
 relationship of arterial change in diameter to change in pressure and include aortic strain
 (relative change in diameter), compliance (absolute change in diameter in response to a
 change in pressure), distensibility (relative change in diameter in response to a change in
 pressure), and the aortic stiffness β index (distensibility using the logarithmic conversion
 of the relative pressure). Applanation tonometry, which uses a probe or tonometer to record
 the pulse wave with a transducer, is the most widely accepted method for estimating PWV and
 both the NIHem (Cardiovascular Engineering, Inc., Norwood, MA USA) and the SphygmoCor (AtCor
 Medical, West Ryde, NSW, Australia) devices have been validated in large cohort trials. Both
 devices will be used, based on local availability.

 Endothelial Function Measurements: Endothelium-dependent reactive hyperaemia index and
 augmentation index will be measured using the EndoPAT 2000 system (Itamar Medical, Caesarea,
 Israel). The protocol includes measures to minimize the influence of the autonomic nervous
 system.

 Pulse Waveform Analysis: Central aortic pressure and pulse pressure will be measured using
 applanation tonometry). Augmentation index will be measured using applanation tonometry and
 Endo-PAT. CAP, PP and AIx can be measured non-invasively using radial or carotid applanation
 tonometry (and Endo-PAT for AIx), calibrated by the peripheral diastolic and mean arterial
 pressure. Both the NIHem system and the SphygmoCor device were used.

 Blood Pressure Phenotype will be measured using conventional standard techniques including
 auscultatory right arm BP measurement, measurement of BP gradient between arm and leg, BP
 response during treadmill exercise stress testing (ET) and ABPM. Based on the auscultatory BP
 and ABPM results, the appropriate children and adult guidelines will be used to classify
 patients. Patients currently on antihypertensive medication will be classified as
 hypertensive.

 Biomarkers: The researchers will measure biomarkers of endothelial function (total oxides of
 nitrogen- NOx and ADMA), inflammation (hs-CRP), vascular wall function (VCAM-1 and IL-1β) and
 vascular remodeling (MMP-2; MMP-9 and TGF-beta1). NOx will be determined by chemiluminescence
 (Sievers NOAnalyzer 280i) and all remaining measurements will be performed with appropriate
 enzyme-linked immunosorbent assay (ELISA) kits: ADMA (Sunred Biological Technology, Shanghai,
 China); hs-CRP (BoosterBio, Pleasanton, USA); VCAM-1; IL-1β; MMP-9; MMP-2 and TGFβ-1
 (RayBiotech, Inc. Norcross, USA).

 Left Ventricular Mass Assessment by CMR. The altered blood pressure phenotype that persists
 after CoA treatment represents an increase in afterload that leads to LV hypertrophy. Our CMR
 protocol will include sequences that allow this quantification.

 Cardiovascular Health Assessment: The researchers will assess health factors (blood pressure,
 total cholesterol, plasma glucose), behaviors (smoking, body mass index BMI, physical
 activity and diet) and family history of cardiovascular disease and risk factors. A
 questionnaire was implemented to assess family history of CV disease and ICVH according to
 the procedures and recommendations of the American Heart Association.

 Statistical Considerations. The treatment groups will be frequency-matched for documented
 confounders. The confounding variables will include: (a) Age at treatment; (b) Current age;
 (c) Bicuspid aortic valve as it is associated with impaired aortic elasticity. Because of the
 relatively large number of matching variables and three treatment groups, matching individual
 subjects was not feasible. During analysis, the treatment groups will be compared for each of
 these confounding variables and appropriate adjustments made, if needed. Differences in the
 confounding variables across the three treatment groups will be evaluated using Fisher's
 exact test for severity of coarctation and the Kruskal-Wallis test for age at treatment,
 current age and bicuspid aortic valve. The primary outcome variable will be carotid-femoral
 PWV assessed by tonometry. Differences in cfPVW across groups will be explored using one-way
 analysis of variance. If differences in matching variables are detected among the groups,
 adjustment will be made using analysis of covariance. Post-hoc analyses will be performed as
 necessary.

 Sample size estimates were obtained based on prior data that show that ascending- descending
 PWV measured by CMR is 3.3±0.6 m/s in normal subjects and 4.7±1.1 m/sec after CoA surgery.22,
 70 Sample size estimates for comparison of PVW between three equal sized treatment groups
 (assuming overall significance level=0.05 and power=0.8) are shown in table 2. The
 investigators plan on recruiting 24 to 30 patients in each group for a total sample size of
 72 to 90.
Inclusion Criteria:

 -  Diagnosis of isthmic coarctation of the aorta;

 -  Current age between 8 (to allow cooperation with study procedures) and 35 years (to
 avoid confounding by aging-related vascular dysfunction); and

 -  Treatment for CoA after 1994, after which all three modalities were in clinical use.

 Exclusion Criteria:

 -  Residual CoA defined by a systolic upper-to-lower extremity BP gradient> 20mmHg;

 -  Co-morbidities that may independently affect vascular function, including associated
 significant congenital heart disease, history of known vasculopathy, genetic syndromes
 or other cardiovascular risk factors;

 -  History of two treatment types for CoA; and

 -  CoA types likely representing a different entity or patients amenable to one single
 treatment type (surgery), including atypical CoA site (such as mid-thoracic or
 abdominal), severe hypoplasia of the aortic arch, and an age of treatment <1 year of
 age.