Impact of Sirolimus as a Primary Immunosuppressant on Myocardial Fibrosis and Diastolic Function Following Heart Transplantation

Abstract

Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P =0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P =0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P =0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P =0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P =0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P =0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.

Modeling Effects of Immunosuppressive Drugs on Human Hearts Using Induced Pluripotent Stem Cell–Derived Cardiac Organoids and Single-Cell RNA Sequencing

“…These findings may explain the long-term benefit of proliferation signal inhibitors (sirolimus) on adverse remodeling observed in this study and by other groups. 3,5 Furthermore, calcineurin inhibitors (tacrolimus) may be associated with a trend toward a profibrotic phenotype in cardiac tissues that may contribute to adverse cardiac remodeling. In summary, combining induced pluripotent stem cell–derived cardiac organoids and single-cell RNA sequencing may provide a platform for future studies to identify more targeted approaches to ameliorate tacrolimus-associated cardiac remodeling and replicate the favorable sirolimus cardiac profile.…”

The impact of mTOR inhibitors in the regression of left ventricular hypertrophy in elderly kidney transplant recipients

“…Raichlin et al 39 . and Alnsasra et al 40 . studied HTR converted to SRL‐based immunosuppression along with CNI withdrawal.…”

“…Alnsasra et al. showed that the conversion to SRL was associated with significant improvement in left ventricular filling pressures and a trend for a more attenuated myocardial fibrosis progression among HTR as compared with continued CNI therapy 40 …”

Current status and outcomes in heart transplantation: a narrative review

“…Other maintenance regimens include mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, when there is concern for renal dysfunction as they lack the renal toxicity associated with CNI. Sirolimus has been shown to have similar effects on myocardial fibrosis compared to CNI and is associated with improvements in diastolic function and pulmonary arterial pressure [104].…”