Hypercholesterolemia Increases Coronary Endothelial Dysfunction, Lipid Content, and Accelerated Atherosclerosis After Heart Transplantation

Abstract

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. Endotheliumdependent relaxations to serotonin, to the ␣ 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. Key Words: endothelium Ⅲ lipids Ⅲ coronary arteries Ⅲ transplantation Ⅲ atherosclerosis T he normal endothelium contributes to the local regulation of vasomotor tone and the maintenance of a nonthrombogenic surface, acts as a selective barrier controlling permeability and transport, and regulates the adhesion and extravasation of neutrophils, monocytes, and lymphocytes 1 and the proliferation of underlying vascular smooth muscle cells. These properties are due to the ability of endothelial cells to secrete endothelium-derived relaxing factors such as nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin. 2 Endothelial dysfunction is a fundamental initial step in the progression of atherosclerosis.Although heart transplantation remains the treatment of choice for medically unresponsive terminal heart disease and is associated with a 5-year survival of Ϸ70%, coronary graft vasculopathy develops in a majority of transplant recipients and is the main cause of death beyond the first year after transplantation. 3 Accelerated atherosclerosis is preceded by reduced dilatation of the coronary artery to endotheliumdependent agonists. 4 This endothelial dysfunction is due to an immunologic injury directed at the endothelial cells and to other factors that cause endothelial activation and trigger a cascade of path...

Impact of Statin Use After Heart Transplantation

“…In porcine heart transplant models, dietinduced hypercholesterolemia resulted in accelerated allograft vessel intimal hyperplasia and increased lipid deposition. 22 In heart transplant patients, statins not only reduce cholesterol levels but also decrease the incidence of graft atherosclerosis. 1,18 Alternatively, cholesterol-independent effects of statins also play a major role in inhibiting allograft coronary artery vasculopathy, which occurs via mechanisms other than atherosclerosis.…”

Arterial Stiffening Influence of Sympathetic Nerve Activity

“…An increase in vessel distensibility is regarded as clinically beneficial because it results into a reduction in pulse pressure (an independent cardiovascular risk factor 17 ) and endothelial trauma, with a reduced atherogenesis. 18 It is not inconceivable, however, that when the increase in distensibility is as abrupt and large as the one seen in the radial artery after transplantation, the resulting marked increase in systo-diastolic vessel excursion may lead to mechanical damage of the vessel.…”

Increased NPC1L1 and serum cholesterol in a chronic rejection rat

“…Allogra vasculopathy may begin because of endothelial damage induced by ischemia at the time of transplantation and accelerate due to hyperlipidemia or other risk factors, as seen in other models of accelerated atherosclerosis [17]. Autopsy studies have shown that the cholesterol content in transplant coronary arteries is 10-fold greater than in native vessels, and clinical studies have associated increased cholesterol levels with a greater risk of TA [2].…”

“…Histologically ,there is arteriosclerosis of the gra vessels, with thickening of the intimal layer resulting in progressive lumen occlusion. Hypercholesterolemia has been found to accelerate the development of these vascular lesions, and is a risk factor for decline in gra function and CR [2,3,17].…”