In addition to short-term effects related to calcium handling, long-term CCM therapy upregulates genes related to calcium cycling and handling, reduces fetal gene expression, and results in reverse remodeling at the tissue level.29, 30, 31 One study of biopsy specimens from patients with HF receiving CCM therapy for 3 months showed increased expression of SERCA2a, phospholamban, and RyR2, indicating favorable changes in gene expression.31 This evidence concerns the gene RYR2 and cerebral cavernous malformation.