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Hypercholesterolemia increases coronary endothelial dysfunction, lipid content, and accelerated atherosclerosis after
L P Perrault1, F Mahlberg, C Breugnot
1Research Center and Department of Surgery, Montreal Heart Institute, Montreal, Quebec, Canada.
Insights
High cholesterol diets worsen heart transplant outcomes by causing endothelial dysfunction and intimal hyperplasia. This hyperlipidemia accelerates graft coronary atherosclerosis, impacting long-term graft survival.
Area of Science:
- Cardiovascular Science
- Transplantation Immunology
- Vascular Biology
Background:
- Hyperlipidemia is a known risk factor for atherosclerosis.
- Endothelial dysfunction and intimal hyperplasia are key components of graft coronary vasculopathy.
- The specific impact of hypercholesterolemia on early post-transplant coronary allografts requires further elucidation.
Purpose of the Study:
- To investigate the effects of hypercholesterolemia on coronary endothelial function in a heart transplant model.
- To assess the impact of hypercholesterolemia on intimal hyperplasia and lipid deposition in coronary arteries of transplanted hearts.
- To determine if hyperlipidemia accelerates atherogenesis in early cardiac allografts.
Main Methods:
- A porcine model of heterotopic heart transplantation was utilized, allowing for study without immunosuppression.
- Donor and recipient swine were fed a high-cholesterol diet before and after transplantation.
- Endothelial function was assessed in organ chambers using various agonists; intimal hyperplasia and lipid content were histologically evaluated.
Main Results:
- Hypercholesterolemia significantly increased total serum cholesterol levels.
- Endothelium-dependent relaxations were impaired in allografted hearts compared to native hearts.
- High cholesterol diet exacerbated endothelial dysfunction, increased intimal hyperplasia, and augmented lipid content in allograft coronary arteries.
Conclusions:
- Hypercholesterolemia induces generalized coronary endothelial dysfunction following heart transplantation.
- Hyperlipidemia significantly increases the prevalence of intimal hyperplasia and lipid accumulation in cardiac allografts.
- These findings indicate that hyperlipidemia accelerates graft coronary atherosclerosis through endothelial-mediated mechanisms.
Abstract:
Hyperlipidemia may increase endothelial damage and promote accelerated atherogenesis in graft coronary vasculopathy. To study the effects of hypercholesterolemia on coronary endothelial dysfunction, intimal hyperplasia, and lipid content, a porcine model of heterotopic heart transplantation, allowing nonacute rejection without immunosuppressive drugs, was used. A high cholesterol diet was fed to donor and recipient swine 1 month before and after transplantation. The endothelial function of coronary arteries of native and transplanted hearts from cholesterol-fed animals was studied in organ chambers 30 days after implantation and compared with endothelial function in arteries from animals fed a normal diet. The total serum cholesterol increased 3-fold in donors and recipients. Endothelium-dependent relaxations to serotonin, to the alpha(2)-adrenergic agonist UK14,304, and to the direct G-protein activator sodium fluoride were decreased significantly in allografted hearts compared with native hearts from both groups. Relaxations to the calcium ionophore A23187 and bradykinin were decreased significantly in allografts from animals fed the high cholesterol diet. The prevalence of intimal hyperplasia was significantly increased in coronary arteries from hypercholesterolemic swine. There was a significant increase in the lipid content of allograft arteries of hypercholesterolemic recipients. Hypercholesterolemia causes a general coronary endothelial dysfunction, increases the prevalence of intimal hyperplasia, and augments the incorporation of lipids in the vascular wall after heart transplantation. Hyperlipidemia accelerates graft coronary atherosclerosis through its effects on the endothelium.