Background:
Late survival after pediatric heart transplantation (HTx) remains poor. Many late deaths are due to “graft failure,” typically in the presence of vasculopathy and diffuse myocardial fibrosis (DMF) - a process associated with ventricular remodeling and heart failure (HF). Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) is a validated measure of DMF in the absence of edema or infiltrative disease, and predicts outcomes of HF and mortality in adults. We hypothesize that ECV is a meaningful biomarker of graft dysfunction following pediatric HTx.
Objective:
To test the association of ECV with histologic myocardial fibrosis after pediatric HTx. We also explored associations of ECV with hemodynamic, echocardiographic, and serum measures of graft function.
Methods:
We prospectively enrolled consecutive HTx recipients who were ≥13 years old and ≥9 months post HTx for ECV quantification at the time of surveillance endomyocardial biopsy (EMB). Fibrosis was quantified on EMB by automated image analysis after picrosirius staining and digital scanning. CMR measures of blood and myocardial T1 from basal and mid short axis slices, along with contemporaneous hematocrit, quantified ECV.
Results:
Nineteen pts (12 male) underwent CMR at a mean age of 18.4 ± 2.8 yrs (range 14.9 - 24.4 yrs) and a mean time after HTx of 10.4 ± 6.6 yrs (1.0 - 20.7 yrs). Four pts were excluded from analysis due to acute rejection (ISHLT grade ≥2R) on concurrent EMB (n=2) or poor quality imaging (n=2). Mean ECV was 27.1 ± 3.8 (20.9 - 32.1). Late gadolinium enhancement was observed in 1 pt. ECV showed moderate correlations with histologic myocardial fibrosis (r=0.61; p=0.02) and serum b-type natriuretic peptide (r=0.66; p=0.008). There was a trend to correlation with pulmonary capillary wedge pressure (r=0.51; p=0.06). We found no associations of ECV with systolic or diastolic function, time after HTx, or graft age.
Conclusions:
We demonstrate a novel association of ECV with histologic myocardial fibrosis and serum and hemodynamic markers of HF after pediatric HTx. Given prior observations of myocardial fibrosis in chronic graft failure, these findings suggest that ECV may be a relevant, noninvasive marker of graft dysfunction and a potential therapeutic target.
Risk factors for, graft failure associated with pulmonary hypertension after pediatric heart transplantation