Mitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia.

There is current awareness about the central role of mitochondrial dysfunction in the development of cardiac dysfunction in systemic inflammatory syndromes, especially in sepsis and endotoxemia. The aim of this work was to elucidate the mechanism that governs the link between the severity of the systemic inflammatory insult and mitochondrial function, analysing the consequences on heart function, particularly in cardiac contractile state. Female Sprague-Dawley rats were subjected to low-grade endotoxemia (i.p. injection LPS 0.5 mg kg-1 body weight) and severe endotoxemia (i.p. injection LPS 8 mg kg-1 body weight) for 6 h. Blood NO, as well as cardiac TNF-α and IL-1ß mRNA, were found increased as the severity of the endotoxemia increases. Cardiac relaxation was altered only in severe endotoxemia, although contractile and lusitropic reserves were found impaired in both treatments in response to work-overload. Cardiac ultrastructure showed disorientation of myofibrillar structure in both endotoxemia degrees, but mitochondrial swelling and cristae disruption were only observed in severe endotoxemia. Mitochondrial ATP production, O2 consumption and mitochondrial inner membrane potential decreases were related to blood NO levels and mitochondrial protein nitration, leading to diminished ATP availability and impairment of contractile state. Co-treatment with the NOS inhibitor L-NAME or the administration of the NO scavenger c-PTIO leads to the observation that mitochondrial bioenergetics status depends on the degree of the inflammatory insult mainly determined by blood NO levels. Unravelling the mechanisms involved in the onset of sepsis and endotoxemia improves the interpretation of the pathology, and provides new horizons for novel therapeutic targets.

Mimetización del precondicionamiento por activación vagal. Efectos sobre la función ventricular en un modelo experimental crónico / Mimicking Preconditioning by Vagal Stimulation. Effectis on Ventricular Function in a Chronic Experimental Model

RESUMEN Introducción: En trabajos previos demostramos que la electroestimulación vagal preisquémica (EVp) es capaz de reducir el tamaño del infarto agudo de miocardio, sin una mejoría significativa sobre la función ventricular dentro de las dos horas de reperfusión. Se desconocen los efectos de esta modalidad de EV sobre la función ventricular izquierda (FVI) a largo plazo. Objetivos: Estudiar si los efectos protectores de la EVp breve sobre el tamaño del infarto agudo repercuten en una mejoría de la FVI en un modelo crónico de isquemia y reperfusión miocárdica. Material y métodos: En ratones FVB se realizó una isquemia miocárdica regional de 45 minutos con 2 horas o 28 días de seguimiento posreperfusión, con o sin 10 minutos de EV preisquémica. Se midió el tamaño del infarto (TI) con cloruro de 2,3,5-trifeniltetrazolio. Se evaluó la FVI mediante ecocardiografía y cateterismo del VI. Resultados: La EVp redujo el TI medido a las 2 horas de reperfusión de 66,8 ± 3,2% a 43,2 ± 1,6% (p < 0,001), sin una respuesta favorable sobre la FVI. A los 28 días, en el grupo con EVp se observó una mejoría en la FVI, evidenciada por una menor presión de fin de diástole del ventrículo izquierdo (4,44 ± 1 vs. 6,91 ± 1 mmHg del grupo control; p < 0,05), mayor fracción de eyección (69,7 ± 2,8% vs. 59 ± 3,2%; p < 0,05), mayor fracción de acortamiento (33,4 ± 2,23% vs. 25,8 ± 1,8%; p < 0,05) y menor tiempo de relajación isovolúmica (25 ± 0,8 mseg vs. 30,3 ± 1,2 mseg; p < 0,05). Conclusiones: En un modelo de isquemia y reperfusión miocárdica en ratones, la mimetización del precondicionamiento isquémico por EV mejora la evolución crónica del infarto y redunda en una mayor recuperación de la FVI.

ABSTRACT Background: Previous studies have shown that preischemic vagal electrostimulation (pVS) reduces acute myocardial infarct size, without a significant improvement on ventricular function within the two-hour reperfusion period. It is unknown which are the long-term effectis of pVS on left ventricular function (LVF). Objectives: The aim of this study was to analyze whether the protective effectis of brief pVS on acute infarct size improves LVF in a chronic myocardial ischemia-reperfusion model. Methods: FVB mice were subjected to 45-minutes regional myocardial ischemia followed by 2 hours of reperfusion or 28-day post-reperfusion follow-up with or without 10-minutes pVS. Infarct size (IS) was measured with 2,3,5-triphenyltetrazolium chloride, and LVF was assessed by echocardiography and left ventricular catheterization. Resultis: Preischemic vagal stimulation reduced IS from 66.8±3.2% to 43.2±1.6% (p <0.001) at 2 hours of reperfusion, without a favorable LVF response. At 28 days, the pVS group exhibited LVF improvement, with lower left ventricular end-diastolic pressure (4.44±1 vs. 6.91±1 mmHg in the control group; p<0.05), higher ejection fraction (69.7±2.8% vs. 59.3±3.2; p<0.05), greater shortening fraction (33.4±2.23 vs. 25.8±1.8%; p<0.05) and lower isovolumic relaxation time (25±0.8 ms vs. 30.3 ±1.2 ms; p<0.05) Conclusions: In a mice model of myocardial ischemia and reperfusion, mimicking ischemic preconditioning by VS improves the chronic outicome of infarction, resulting in greater LVF recovery.

Irinotecan-eluting stents inhibited neointimal proliferation in hypercholesterolemic rabbit aortas.

OBJECTIVE: To assess the effect of irinotecan-eluting stents (IS) on neointimal growth in the aortas of hypercholesterolemic rabbits and to determine other local histopathological effects such as necrosis, fibrin, and inflammatory reaction. METHODS: Phosphorylcholine-coated stents were deployed in the aortas of hypercholesterolemic rabbits. Group 1 (control; n = 8) received unloaded stents, group 2 (n = 7) and group 3 (n = 9) received IS with 0.046 mg and 1.29 mg of irinotecan, respectively. Eight weeks after implantation the rabbits were killed. Neointimal thickness (NT) was assessed by morphometry. Semiquantitative injury score (from 0 to 3+) was used to analyze inflammatory infiltrate, fibrin deposits, and necrosis in the stented segments. RESULTS: NT was reduced only in high-doses IS (G1, 167.4 +/- 20.8 mu; G2, 170.24 +/- 21.2 mu; G3, 111.56 +/- 12.7 mu; P < 0.05, G3 vs G1 and G2). Necrosis decreased significantly with IS [1.00 +/- 0.10 in G1 to 0.33 +/- 0.07 and 0.02 +/- 0.01 in G2 and G3, respectively] only in the media layer. The inflammatory infiltrate was present in the three layers of aortas from G1, but only decreased significantly in the intimae layer of the high-dose group [1.50 +/- 0.15 in G1 vs 1.00 +/- 0.18 in G3, P < 0.05]. CONCLUSION: Stents loaded with high-dose irinotecan inhibit NT in the aortas of hypercholesterolemic rabbits. This effect was accompanied by decreased inflammatory infiltrate and media necrosis.