Atherogenesis takes place in cholesterol-fed rabbits when circulating concentrations of endogenous cortisol are increased and inflammation suppressed.

Atherosclerosis is an inflammatory disease, but the response of the endogenous anti-inflammatory system during this process has not been evaluated previously. Cortisol is the end product of this anti-inflammatory system, but is also able to activate cellular processes that induce atherogenesis; however, it is unknown whether atherogenesis occurs when circulating concentrations of endogenous cortisol are increased or when they are decreased. We have evaluated the counter-regulatory responses of cortisol and interleukin-1beta (IL-1beta) during the short- and long-term responses to vascular injury in rabbits fed a 2% cholesterol diet. In the short-term group (n=18), serum cortisol and IL-1beta concentrations were measured after 10, 20 and 30 days. Rabbits developed hypercholesterolemia and hypercortisolemia, with only modest increases in IL-1beta. Although inflammation was low-grade, atherogenesis took place, with subintimal lipid accumulation evident on day 30. In the second group (n=18), we evaluated variables after 40, 60 and 90 days. This group developed hypercholesterolemia, but serum cortisol concentrations were inappropriately normal, while IL-1beta concentrations were elevated 8.6-fold; advanced atherosclerotic plaques were evident on days 60 and 90. These results show that atherogenesis occurs when high endogenous cortisol levels are suppressing inflammation, and are consistent with a promotion of early atherogenesis by high cortisol concentrations.

Intracoronary brachytherapy after stenting de novo lesions in diabetic patients: results of a randomized intravascular ultrasound study.

OBJECTIVES: We studied the efficacy of intracoronary brachytherapy (ICB) after successful coronary stenting in diabetic patients with de novo lesions. BACKGROUND: Intracoronary brachytherapy has proven effective in preventing recurrences in patients with in-stent restenosis. However, the role of ICB for the treatment of de novo coronary stenoses remains controversial. METHODS: Ninety-two patients were randomized to either ICB or no radiation after stenting. Primary end points were in-stent mean neointimal area (primary end point of efficacy) and minimal luminal area of the entire vessel segment (primary end point of effectiveness), as assessed by intravascular ultrasound at six-month follow-up. Quantitative coronary angiography analysis was performed at the target, injured, irradiated, and entire vessel segments. RESULTS: At follow-up, the in-stent mean neointimal area was 52% smaller in the ICB group (p < 0.0001). However, there was no difference in the minimal luminal area of the vessel segment (4.5 +/- 2.4 mm2 vs. 4.4 +/- 2.1 mm2). Restenosis rates increased progressively by the analyzed segment in the ICB group: target (7.1% vs. 20.9%, p = 0.07), injured (9.5% vs. 20.9%, p = NS), irradiated (14.3% vs. 20.9%, p = NS), and vessel segment (23.8% vs. 25.6%, p = NS). At one year, 1 cardiac death, 6 myocardial infarctions (MIs) (3 due to late stent thrombosis), and 10 target vessel revascularizations (TVRs) (6 due to the edge effect) occurred in the ICB group, whereas in the nonradiation group, there were 11 TVRs and no deaths or MIs. CONCLUSIONS: Intracoronary brachytherapy significantly inhibited in-stent neointimal hyperplasia after stenting in diabetic patients. However, clinically this was counteracted by the occurrence of the edge effect and late stent thrombosis.

Is there a Role for Cortisol in the Accumulation of Lipids in the Intima a Crucial Step of Atherogenesis?

Accumulation of lipids in the intima is the initial and crucial step in atherogenesis, but, this step is not always synonymous with atherogenesis. The factors that trigger the mechanisms modulating lipid accumulation in the vessel wall and in the subsequent development of atherosclerotic plaque remain unclear. In this review we evaluate whether atherogenesis is modulated by cortisol, the end hormone of the stress-related anti-inflammatory system. The amount of accumulated lipids in the intima depends on the balance between the penetration and efflux of cholesterol from the artery wall. We assess whether cortisol is involved in this balance. Cortisol can increase the penetration of lipids, and, simultaneously, might reduce their efflux from the intima. We also report a critical analysis on whether atherogenesis, which has a local nature, can be modulated by a systemic factor. In addition, we comment on the synergistic action of cortisol with insulin in atherogenesis, and consider relevant recent clinical evidence regarding the role of cortisol in atherosclerosis. Glucocorticoids, by triggering the mechanisms that favor the penetration of lipids in the intima, and modulating factors that control the efflux of cholesterol from the artery wall, may lead to the formation of atherosclerotic plaques. Thus, cortisol may have a role in atherogenesis. This may have important clinical, therapeutic and preventive implications.

Left ventricular assist devices in patients with end-stage heart failure: suggestion of an alternative treatment based on clinically well-known concepts.

Encouraging results were obtained by using left ventricular assist devices (LVADs) in patients with end-stage heart failure (HF) that exhibits extremely high mortality and who were not candidates for heart transplantation. By using this so-called destination therapy (DT), a substantial percentage of these patients achieved sufficient improvement in cardiac function to permit the explantation of the device. The combination of mechanical and pharmacological therapy increased the frequency and durability of myocardial recovery as compared with other therapeutic approaches. Although cardiac transplantation, LVADs, and cardiac resynchronization therapy have provided a major advance in DT, their limitations stimulate the search for alternative therapies. We discuss the limitations of these 3 treatment options for end-stage HF. Also, we propose and discuss the possible advantages of a new intracorporeal procedure that works continuously as intraaortic balloon counterpulsation without an extracorporeal or intracorporeal computer-controlled mechanism.

The role of the stress-related anti-inflammatory hormones ACTH and cortisol in atherosclerosis.

Chronic stress and probably the accompanying changes in personal behaviours can influence life expectancy. The role of adrenocorticotropic hormone (ACTH) and cortisol in atherosclerosis is not widely accepted and incompletely characterized. Several reports support a role of these hormones in atherogenesis by modulating the function of vascular endothelium, the recruitment of circulating monocytes to the artery wall and their differentiation into macrophages- foam cells, by controlling the expression of pro- and anti-inflammatory interleukins. Previous reports suggested an important role of ACTH and cortisol in the modulation of atherosclerotic plaque progression by removal of excess free cholesterol from macrophages. Studies suggested a crucial role of these hormones on the development of acute coronary syndromes [(ACS); unstable angina, and acute myocardial infarction] and stroke, by modulating platelet aggregation and thrombus formation. This review focuses on the identified mechanisms and roles of ACTH and cortisol in atherogenesis, progression of atherosclerosis and the development of ACS. Finally, it proposes experimental studies to evaluate the therapeutic potential of new glucocorticoid antagonists, the effects that may derive from the inhibition cortisol synthesis and the role of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors in atherogenesis, progression of atherosclerosis and the development of ACS. These hormones may be a possible additional target for the prevention and treatment of atherosclerosis.

The role of intracellular 3'5'-cyclic adenosine monophosphate (cAMP) in atherosclerosis.

Intracellular cAMP is an ubiquitous intracellular second messenger that regulates important cellular functions. Intracellular cAMP levels are regulated by the enzymes adenylyl cyclase and phosphodiesterases. The role of cAMP in atherosclerosis is not widely accepted and incompletely characterized. Several reports support a role of cAMP in atherogenesis by modulating the function of vascular endothelium, the production of reactive oxygen species, the recruitment of circulating monocytes to the artery wall and their differentiation into macrophages- foam cells, by controlling the expression of pro- and anti-inflammatory interleukins, and regulating serum levels of triglycerides and cholesterol. Previous reports suggested an important role of cAMP in the modulation of atherosclerotic plaque progression by removal of excess free cholesterol from macrophages by inducing the ABCA1 secretory pathway and reducing circulating levels of cholesterol. Studies suggested a crucial role of cAMP on the development of acute coronary syndromes [(ACS); unstable angina, and acute myocardial infarction] and stroke, by modulating platelet aggregation and thrombus formation and the expression of metalloproteinases. This review focuses on the identified mechanisms and roles of cAMP in the prevention of atherosclerosis, atherogenesis, and progression of atherosclerosis and the development of ACS. Finally, it provides evidence that showed the beneficial effects that may derive from the inhibition of phosphodiesterase III and activation of adenylyl cyclase and subsequent elevation of cAMP levels. Thus, cAMP may be a possible target for the prevention and treatment of atherosclerosis.

Acute arterial thrombosis in the absence of inflammation: the stress-related anti-inflammatory hormone ACTH participates in platelet-mediated thrombosis.

OBJECTIVE: Despite the reciprocal relationship that exists between inflammation and thrombosis, we asked whether thrombosis can develop without inflammation, and whether stress-related hormones (ACTH and cortisol) influence platelet-mediated thrombosis. METHODS: We investigated the role of ACTH and cortisol in platelet aggregation, as well as on the circulating levels of IL-6 in pigs subjected to different treatments. In control animals, deep vessel wall injury (DVWI) was induced in the right common carotid artery, while in the animals under study DVWI was induced 60 min after ACTH administration (subgroup 1) or not at all (subgroup 2). In an ex vivo study we evaluated whether ACTH or cortisol modulates platelet aggregation. Indeed, we assessed whether blocking the P2Y platelet receptors inhibits the effect of ACTH on platelet aggregation. Finally, we assessed whether ACTH mobilizes intracellular calcium and modulates intracellular cAMP in platelets ex vivo. RESULTS: We found that the suppression of inflammation following ACTH administration was accompanied by acute arterial thrombosis in the zone of injury in vivo. Furthermore, ACTH but not cortisol amplifies the platelet aggregation induced ex vivo by agonists. Platelets do not express ACTH receptors which may explain why ACTH does not reduce intracellular levels of cAMP in platelets. Nevertheless, supraphysiological concentrations of ACTH increase calcium mobilization in platelets. CONCLUSION: These results indicate for the first time that ACTH may fulfil an important role in acute arterial thrombosis by increasing the platelet aggregation induced by agonists, probably via a G(q)-coupled pathway.

Increases of corporal temperature as a risk factor of atherosclerotic plaque instability.

BACKGROUND: This work explores for the first time the effects of temperature increments on the development of high shear stresses between plaque and arterial wall due to their different dilatational properties. Data from the literature report febrile reactions prior to myocardial infarction in patients with normal coronary arteries and that coronary syndromes seem to be triggered by bacterial and viral infections, being fever the common symptom. METHODS: The thermo-mechanical behavior of thoracic aortas of New Zealand White rabbits with different degrees of atherosclerosis was measured by means of pressure-diameter tests at different temperatures. In addition, specific measurements of the thermal dilatation coefficient of atheroma plaques and of healthy arterial walls were performed by means of tensile tests at different temperatures. RESULTS: Results show a different thermo-mechanical behavior, the dilatation coefficient of atheroma plaque being at least twice that of the arterial wall. The calculation of temperature-induced mechanical stress at the plaque-vessel interface yielded shear stress levels enough to promote plaque rupture. CONCLUSIONS: Increases of corporal temperature either local--produced by the inflammatory processes associated with atherosclerosis--or systemic--by febrile reactions--can play a role in increasing the risk of acute coronary syndromes, and they deserve a more comprehensive study.

Pathological effects of pulmonary vein beta-radiation in a swine model.

INTRODUCTION: Atrial fibrillation (AF) may be triggered by ectopic beats originating in sleeves of atrial myocardium entering the pulmonary veins (PVs). PV isolation by means of circumferential ostial or atrial radiofrequency ablation is an effective but also a difficult and long procedure, requiring extensive applications that can have serious potential complications. Our objective was to examine pathological effects of PV beta-radiation, particularly the ability to destroy PV myocardial sleeves without inducing PV stenosis and other unwanted effects, in order to establish its potential feasibility for the treatment of AF. METHODS AND RESULTS: Ten minipigs were studied. A phosphorus-32 source wire centered within a 2.5-mm diameter balloon catheter (Galileo III Intravascular Radiotherapy System, Guidant, Santa Clara, CA, USA) was used to deliver beta-radiation to the superior wall of the right PV trunk. Pathological analysis was performed either immediately after ablation (2 pigs) or 81 +/- 27 days later (8 pigs). Acute effects of PV beta-radiation consisted of endothelial denudation covered by white thrombus, elastic lamina disruption, and PV sleeve necrosis. Late effects consisted of mild focal neointimal hyperplasia that reduced the PV luminal area by only 1.3 +/- 1.8%, elastic lamina thickening, and PV sleeve fibrosis. Four of these 8 PVs were completely re-endothelized. Lesions were transmural in 6 of 10 radiated PVs and segmental, involving 28 +/- 7% of the right PV perimeter. CONCLUSION: Intravascular beta-radiation can induce transmural necrosis and fibrosis of PV myocardial sleeves without PV stenosis and other unwanted effects, which supports a potential usefulness of this energy source in the treatment of AF.

Efecto del AMPC sobre la función de las células endoteliales y la proliferación fibromuscular tras la lesión de las arterias carótida y coronaria en un modelo porcino / Effect of cAMP on Endothelial Cell Function and Fibromuscular Proliferation in an Injured Swine Carotid and Coronary Artery

Introducción y objetivos. El adenosinmonofosfato cíclico (AMPc) restablece la función de barrera del endotelio vascular y previene la liberación de citocinas proinflamatorias. Evaluamos in vivo si el aumento de las concentraciones de AMPc acelera la reendotelización y atenúa la proliferación fibromuscular. Métodos. Media hora antes de causar la lesión de ambas arterias carótidas con balón, 5 cerdos fueron tratados con 2 ml (10 mg) intravenosos en bolo de forskolin, un activador de la adenilciclasa, y otros cinco con 2 ml de suero fisiológico. Estos animales fueron sacrificados a los 8 días y se valoró el grado de reendotelización. En otros 19 cerdos se causó con aterotomo la lesión de la arteria coronaria descendente anterior. Nueve animales fueron tratados con forskolin en bolo y otros 10 con suero fisiológico. Se midió el AMPc intraleucocitario basal, a los 28 y 60 min de administrar el suero o el forskolin, y a los 90 de causar la lesión de la coronaria descendente anterior. Estos animales fueron sacrificados a las 4 semanas y se valoraron el grado de reestenosis y el remodelado arterial geométrico en ambos subgrupos. Resultados. La reendotelización fue superior en el grupo tratado que en el control (p = 0,02) y el número de células CD31 positivas fue significativamente superior en el grupo de estudio (38 ñ 11 células) que en el control (11 ñ 9 células). El grado de lesión causado con el aterotomo fue similar en la totalidad de las arterias. En el grupo control se produjo reestenosis en el 40 por ciento de los animales. El análisis de correlación demostró que tanto en el grupo de estudio como en el control las concentraciones de AMPc elevadas se relacionan con una menor proliferación fibromuscular y un aumento del diámetro de la luz del vaso lesionado. Conclusiones. Nuestros resultados sugieren que el aumento de las concentraciones de AMPc incide en la reendotelización precoz de los segmentos lesionados. El AMPc intracelular puede condicionar el remodelado del vaso y el calibre de su luz (AU)