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Time course of coronary endothelial dysfunction in acute untreated rejection after heterotopic heart transplantation
L P Perrault1, J P Bidouard, P Janiak
1Cardiovascular Division, Institut de Recherches Servier, Suresnes, France.
Insights
Endothelial dysfunction in heart transplant rejection worsens over time, initially affecting G-proteins and leading to intimal hyperplasia. This dysfunction plays a role in developing coronary graft vasculopathy.
Area of Science:
- Cardiology
- Transplantation Immunology
- Vascular Biology
Background:
- Endothelial dysfunction is an early indicator of atherosclerosis and graft coronary artery disease post-heart transplantation.
- Acute rejection of the endothelium may contribute to the development of graft vasculopathy.
- Understanding the timeline and mechanisms of endothelial dysfunction in acute rejection is critical.
Purpose of the Study:
- To investigate the time course and mechanisms of coronary endothelial dysfunction in acute, untreated heart transplant rejection.
- To utilize a swine model to accurately assess these changes.
Main Methods:
- A swine model of heterotopic heart transplantation was employed, with animals monitored 1, 5, 9, and 14 days post-transplant.
- Endothelial function of coronary arterial rings was assessed using organ chambers.
- Histomorphometric studies evaluated intimal hyperplasia in allograft coronary arteries.
Main Results:
- Endothelium-dependent relaxations to serotonin and UK 14304 (Gi-protein coupled) progressively deteriorated.
- By day 14, relaxations to A23187, ADP, and bradykinin were also reduced, indicating broader endothelial dysfunction.
- Progressive intimal hyperplasia was observed, increasing from 29% to 61.5% between days 5 and 14.
Conclusions:
- Endothelial dysfunction in acute rejection develops after 5 days, initially involving G-proteins and worsening over time.
- The progression of intimal hyperplasia correlates with endothelial dysfunction.
- Endothelial dysfunction appears to play a permissive role in the development of acute coronary graft vasculopathy.
Background:
Endothelial dysfunction is one of the early events leading to atherosclerosis. It occurs early after orthotopic heart transplantation and precedes the appearance of accelerated graft coronary artery disease believed to stem from chronic rejection of the endothelium. Acute rejection may contribute to the development of graft vasculopathy.
Methods:
To assess the time course and specific mechanisms of coronary endothelial dysfunction in acute untreated rejection, a swine model of retroperitoneal heterotopic heart transplantation was used. Large white swine (age 10 +/- 2 weeks, weight 25 +/- 5 kg) were serum-typed for class I antigen of the swine leukocyte antigen system and selected to ensure a similar degree of incompatibility. Donor hearts were preserved with normothermic blood cardioplegia and regional hypothermia; the mean ischemic time was 64 +/- 15 minutes. Myocardial contractility decreased from day 5 (normal) to day 14 (weak), but electrical activity was preserved. All coronary arteries were patent, and International Society for Heart and Lung Transplantation grade 4 rejection was present in all hearts beyond 5 days. The endothelial function of epicardial coronary arterial rings of native and transplanted hearts was studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 5, 9, and 14 days after transplantation.
Results:
Maximal endothelium-independent relaxations were unaffected at all stages. Endothelium-dependent relaxations to serotonin and alpha 2-adrenergic agonist UK 14304 (which activate receptors coupled to Gi-proteins) and to sodium fluoride (a direct G-protein activator) deteriorated progressively over time. At 14 days maximal relaxations to the calcium ionophore A23187, adenosine diphosphate, and bradykinin were also reduced, but to a lesser degree than those to serotonin and sodium fluoride. Histomorphometric studies of the allograft coronary artery rings showed progressive intimal hyperplasia from day 5 to day 14, with an increase in the incidence from 29% +/- 8.3% to 61.5% +/- 12%.
Conclusions:
These studies show that endothelial dysfunction in untreated acute rejection after heart transplantation develops beyond 5 days and initially involves G-proteins; the dysfunction worsens over time to finally affect all endothelial mechanisms and vascular smooth muscle. The progression of the associated intimal hyperplasia parallels the alteration in endothelial function, suggesting a permissive role of the dysfunction in the development of this acute form of coronary graft vasculopathy.