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Published on: November 2, 2019
Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: modulation by sirolimus
Luciano Potena1, William F Fearon, Karsten Sydow
1Department of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Insights
Elevated asymmetric dimethylarginine (ADMA) levels predict intimal hyperplasia after heart transplantation. Sirolimus treatment, compared to mycophenolate mofetil, reduced ADMA and cardiac allograft vasculopathy risk.
Area of Science:
- Cardiology
- Transplantation Immunology
- Vascular Biology
Background:
- Cardiac allograft vasculopathy (CAV) is a primary cause of mortality post-heart transplantation (HT).
- Reduced nitric oxide bioavailability contributes to endothelial dysfunction and structural changes in CAV.
- Asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is implicated in endothelial pathobiology.
Purpose of the Study:
- To investigate the association between ADMA concentrations and CAV progression in the first year after HT.
- To evaluate the impact of immunosuppressive agents (mycophenolate mofetil vs. sirolimus) on ADMA levels and CAV development.
Main Methods:
- Thirty-two heart transplant recipients underwent intravascular ultrasound at 1 month and 1 year post-HT.
- Immunosuppression regimens included mycophenolate mofetil (MMF) or sirolimus.
- Primary outcome measures were change in intimal volume and vascular remodeling.
Main Results:
- Plasma ADMA levels correlated with the development of intimal hyperplasia (RR 2.72, P=0.038).
- ADMA levels >0.70 micromol/L identified patients with intimal hyperplasia.
- Sirolimus treatment was associated with lower ADMA levels (0.65 vs. 0.77 micromol/L, P<0.01) and reduced intimal hyperplasia (RR 0.08, P=0.01) compared to MMF.
Conclusions:
- Elevated plasma ADMA is linked to coronary intimal hyperplasia in CAV, highlighting the role of nitric oxide synthase inhibition.
- Sirolimus use, versus MMF, is associated with lower ADMA levels and a decreased risk of accelerated CAV.
Background:
Cardiac allograft vasculopathy (CAV) is a major cause of death after heart transplantation (HT). The reduced bioavailability of endothelium-derived nitric oxide may play a role in endothelial vasodilator dysfunction and thus in the structural changes characterizing CAV. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. It was hypothesized that ADMA concentrations may influence CAV progression during the first postoperative year.
Methods:
Thirty-two consecutive HT recipients underwent intravascular ultrasound evaluation at month 1 and year 1 after HT. Immunosuppression included mycophenolate mofetil (MMF, n=16) and sirolimus (n=16). Change in intimal volume greater than the median and vascular remodeling were major outcome measures.
Results:
Plasma ADMA levels were associated with subsequent development of intimal hyperplasia (risk ratio [95% confidence interval] =2.72 [1.06-6.94]; P=0.038), and plasma ADMA levels greater than 0.70 micromol/L most accurately identified patients who would have developed intimal hyperplasia. However, ADMA levels did not correlate with negative coronary remodeling. Treatment with sirolimus, as compared with MMF, was associated with significantly lower ADMA levels (0.65+/-0.12 vs. 0.77+/-0.10 micromol/L; P<0.01) and less intimal hyperplasia (risk ratio [95% confidence interval] = 0.08 [0.01-0.56]; P=0.01).
Conclusions:
Elevated plasma ADMA is associated with coronary intimal hyperplasia, supporting the importance of nitric oxide synthase inhibition in CAV pathogenesis. Treatment with sirolimus (rather than MMF) is associated with lower ADMA levels and reduced risk of accelerated CAV.
