Genetic Deletion of Galectin-3 Alters the Temporal Evolution of Macrophage Infiltration and Healing Affecting the Cardiac Remodeling and Function after Myocardial Infarction in Mice.

We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3-/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. At 1 week post-MI, lack of Gal-3 markedly attenuated F4/80+ macrophage infiltration and significantly increased the expression of Mrc1 and Chil1, markers of M2 macrophages at the MI zone. Levels of IL-10, IL-6, and matrix metalloproteinase-2 were significantly increased, whereas tumor necrosis factor-α, transforming growth factor-ß, and fibrosis were remarkably attenuated at the infarct zone. In Gal-3 knockout mice, scar thinning ratio, expansion, and cardiac remodeling and function were severely affected from the onset of MI. At 4 weeks post-MI, the natural evolution of fibrosis in Gal-3 knockout mice was also affected. Our results suggest that Gal-3 is essential for wound healing because it regulates the dynamics of macrophage infiltration, proinflammatory and anti-inflammatory cytokine expression, and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 affected the dynamics of wound healing, thus aggravating the evolution of remodeling and function.

Early administration of Enalapril prevents diastolic dysfunction and ventricular remodeling in rabbits with myocardial infarction.

We aimed to investigate the role of early administration of Enalapril (Enal) on post-myocardial infarction (MI) ventricular remodeling and diastolic dysfunction in rabbits. White New Zealand rabbits that underwent coronary artery ligature or Sham were divided in three experimental groups: (1) Sham, (2) MI, and (3) MI+Enal. Enal was given by gavage at a dose of 10mg/kg/day starting at 3h after surgery for 35days. At the end of the protocol, we measured (1) mean arterial pressure, (2) left ventricular (LV)+dP/dtmax, (3) LV end-diastolic pressure (LVEDP) and isovolumic relaxation (Tau), (4) LV dimensions, (5) LV ejection and shortening fraction, (6) infarct size (Masson's trichrome-stained slices), (7) fibrosis in the infarct and remote zone (Picrosirius red-stained slices), and (8) myocyte cross-sectional area (MCSA) in WGA-stained section. Enal reduced the mean arterial pressure by 30% as compared with untreated animals and Sham (P<.05). MI reduced LV+dP/dtmax and LV-dP/dtmax (mmHg/s), increased LVEDP (mmHg), Tau (ms), and t50 (ms) values, suggesting a decrease in the relaxation rate. LV end-diastolic dimension and LV end-systolic dimension (LVESD, mm) increased in untreated MI (P<.05 vs. Sham). In contrast, Enal markedly prevented post-MI diastolic dysfunction by significantly decrease LVEDP from 8.2±0.2 to 5.1±0.3mmHg, Tau from 19.8±0.8 to 15.3±0.9ms, and t50 from 12.4±0.5 to 9.6±0.8ms as well as reduced LVESD from 15±1.1 to 12±0.8mm (P<.05 MI vs. MI+Enal). Collagen concentration in the scar was unaffected, but chronic treatment with Enal prevented myocardial fibrosis and MCSA in the remote zone. In summary, chronic early administration of Enal to rabbits with experimental MI has a favorable effect on ventricular remodeling and diastolic function by reducing MCSA and fibrosis, without affecting the wound healing.

Effects of Endurance Training on Myocardial Hypertrophy and Ventricular Function in a Transgenic Mouse Model with sympathetic Hyperactivity / Efectos del ejercicio intenso sobre la hipertrofia miocárdica y la función ventricular en un modelo de ratón transgénico con hiperactividad simpática

Background: Previous studies have shown that endurance training (ET) reduces inotropic, chronotropic and lusitropic reserve in normal mice. Objective: The aim of this study was to evaluate the effect of endurance training on the inotropic and chronotropic reserve of trans-genic mice with sympathetic hyperactivity induced by overexpression of the cardiac GSα protein. Methods: Endurance training consisted in two daily 90-min sessions, 6 days/week, during 4 weeks. Four experimental groups were formed: 1) non-transgenic sedentary (nonTG Sed); 2) transgenic sedentary (TG Sed); 3) nonTG+ET and 4) TG+ET. Results: Endurance training induced myocardial hypertrophy [left ventricular weight (g)/tibial length (mm)] from 5.3±0.3 and 5.5±0.2 in nonTG Sed and TG Sed to 6.8±0.1 and 6.8±0.3 in nonTG+ET and TG+ET, respectively (p<0.05 nonTG Sed vs. nonTG+ET and TG Sed vs. TG+ET). Isoproterenol administration (56 ng/kg) increased +dP/dtmax by 63±10% in nonTG Sed (p<0.05 vs. baseline), 34±2% in TG Sed (p<0.05 vs. baseline and p<0.05 vs. nonTG Sed), 36±7% in non TG+ET (p<0.05 vs. base-line) and 36±7% in TG+ET (p<0.05 vs. baseline). Heart rate (beats/min) increased from 301±15 to 528±37 in nonTG Sed (p<0.05 vs. baseline), from 519±57 to 603±41 in TG Sed, from 300±16 to 375±20 in nonTG+ET (p<0.05 vs. baseline) and from 484±18 to 515±21 in TG+ET. Interstitial collagen was similar among groups. Conclusions: These results suggest that endurance training decreases inotropic and chronotropic reserve without generating struc-tural changes associated to pathological hypertrophy. The presence of sympathetic hyperactivity does not modify this response.

Introducción: En estudios previos mostramos que el ejercicio intenso (EI) reduce la reserva inotrópica, cronotrópica y lusitrópica en ratones normales. Objetivo: Evaluar el efecto del ejercicio intenso sobre la reserva inotrópica y cronotrópica en un modelo de ratones transgénicos con sobreexpresión cardíaca de la proteína Gsα, que induce un cuadro de hiperactividad simpática. Material y métodos: El ejercicio consistió en dos sesiones diarias de 90 minutos de natación, 6 días/semana durante 4 semanas. Se utilizaron cuatro grupos experimentales: 1: sedentario no transgénico (noTG Sed); 2: sedentario TG (TG Sed); 3: noTG+EI y 4: TG+EI. Resultados: El ejercicio indujo el desarrollo de hipertrofia miocárdica [índice peso del ventrículo izquierdo (g)/longitud de la tibia (mm)] desde 5,3±0,3 y 5,5±0,2 en noTG Sed y TG Sed a 6,8±0,1 y 6,8±0,3 en noTG+EI y TG+EI, respectivamente (p<0,05 noTG Sed vs. noTG+EI y TG Sed vs. TG+EI). La administración de isoproterenol (56 ng/kg) incrementó la +dP/dtmáx 63% ±10% en noTG Sed (p<0,05 vs. basal); 34% ±2% en TG Sed (p<0,05 vs.basal y p< 0,05 vs. noTG Sed); 36% ±7% en noTG+EI (p<0,05 vs. basal) y 36% ±7% en TG+EI (p<0,05 vs.basal). La frecuencia cardíaca aumentó de 301±15 a 528±37 latidos/min en noTG Sed (p<0,05 vs. basal), de 519±57 a 603±41 latidos/min en TG Sed, de 300±16 a 375±20 en noTG+EI (p<0,05 vs. basal) y de 484±18 a 515±21 en TG+EI. El colágeno intersticial fue similar entre los grupos. Conclusiones: Estos resultados sugieren que el ejercicio intenso disminuye la reserva inotrópica y cronotrópica sin generar cambios estructurales vinculados a la hipertrofia patológica. La presencia de hiperactividad simpática no modifica esta respuesta.

Efecto del déficit de galectina-3 sobre la remodelación ventricular posoclusión coronaria en ratones / Effect of Galectin-3 Deficit on Ventricular Remodeling After Coronary Occlusion in Mice

Introducción: La galectina-3 (Gal-3) es una lectina que regula la respuesta inmune. Sin embargo, su rol en la remodelación y la función ventricular posinfarto de miocardio (IM) se desconoce. Objetivo: Estudiar si el déficit de Gal-3 empeora la remodelación y la función ventricular pos-IM en ratones. Material y métodos: Se utilizaron ratones machos Gal-3 KO y su respectivo control C57 con ligadura de la coronaria descendente anterior o sham. Se conformaron cuatro grupos experimentales: C57 sham, Gal-3 KO sham, C57 IM y Gal-3 KO IM. A los 7 días poscirugía se les realizó ecocardiografía seguida de eutanasia y autopsia; se cuantificó el tamaño del IM y la fibrosis en cortes teñidos con tricrómico de Masson y picrosirius red, respectivamente, el infiltrado de macrófagos y la expresión de IL-6. Resultados: Los diámetros del ventrículo izquierdo se incrementaron significativamente en el grupo C57 IM respecto del sham y dicho incremento fue aún mayor en el grupo Gal-3 KO IM. Además, la fracción de eyección disminuyó desde 47% ± 2% a 37% ± 3% en C57 IM y Gal-3 KO IM, respectivamente (p < 0,02). El tamaño del IM aumentó desde 39,4% ± 5% en los ratones C57 IM a 66,8% ± 5% en los animales Gal-3 KO (p = 0,002). El infiltrado de macrófagos y la fibrosis en el área del IM se redujeron en los ratones Gal-3 KO IM (p < 0,001 C57 IM vs. Gal-3 KO IM), mientras que la concentración de IL-6 en la pared libre del ventrículo izquierdo fue similar entre grupos (p = ns). Conclusiones: La deleción de Gal-3 es un factor importante para la cinética del proceso reparativo regulando el infiltrado de macrófagos y el grado de fibrosis de la zona infartada, como también en la evolución temprana de la remodelación pos-IM.

Background: Galectin-3 (Gal-3) is a lectin that regulates the immune response. However, its role in remodeling and ventricular function after myocardial infarction (MI) is unknown. Objective: The purpose of this study was to analyze whether Gal-3 deficit impairs remodeling and ventricular function after MI in mice. Methods: Male Gal-3 KO mice and their respective C57 controls underwent anterior descending coronary artery ligation or sham operation. Animals were then divided into four experimental groups: 1) C57 sham; 2) Gal-3 KO sham; 3) C57 MI and 4) Gal-3 KO MI. Seven days after surgery, an echocardiography was performed followed by euthanasia. Heart samples were collected to measure MI size and fibrosis using Masson's trichrome and picrosirius red, respectively, and assess macrophage infiltration and IL-6 expression. Results: Left ventricular diameters were significantly increased in the C57 MI group compared with sham animals and the increase was even higher in the Gal-3 KO MI group. Moreover, ejection fraction decreased to 47%±2% in C57 MI and 37%±3% in Gal-3 KO MI mice (p<0.02), and infarct size increased from 39.4%±5% in C57 MI to 66.8%±5% in Gal-3 KO MI animals (p=0.002). Macrophage infiltration and fibrosis in the MI area were significantly reduced in Gal-3 KO MI mice (p<0.001 C57 MI vs. Gal-3KO MI) without changes of IL-6 concentration in the left ventricular free wall (p=ns). Conclusions: Gal-3 gene deletion is an important factor in repair kinetics, regulating macrophage infiltration and the degree of fibrosis in the infarct area, as well as early remodeling after MI.

Efectos del ejercicio intenso sobre la función ventricular basal y la respuesta inotrópica, cronotrópica y lusitrópica en ratones / Effects of Strenuous Exercise on Baseline Ventricular Function and Inotropic, Chronotropic and Lusitropic Response in Mice

Introducción El ejercicio leve a moderado reduce los factores de riesgo cardiovascular, mejora estados patológicos previamente establecidos y produce el desarrollo de hipertrofia cardíaca adaptativa. Sin embargo, la respuesta del miocardio frente a un tipo de ejercicio intenso no es del todo conocida. Objetivo Estudiar la función ventricular basal y la reserva miocárdica (respuesta inotrópica, cronotró-pica y lusitrópica frente a un agonista ß-adrenérgico como el isoproterenol) luego de un tipo de ejercicio intenso tanto in vivo como in vitro en ratones. Material y métodos Se utilizaron ratones macho de tres meses de edad de la cepa FVB. El protocolo de ejercicio consistió en dos sesiones diarias de 90 minutos de natación, 6 días/semana durante 4 semanas. Se conformaron dos grupos experimentales: 1) Sedentario: no realiza ejercicio y 2) Ejercicio: realiza protocolo completo de natación intenso. Resultados Al finalizar el protocolo hubo un incremento de la masa ventricular izquierda del 27,9% ± 4%, con función ventricular basal conservada. Sin embargo, hubo una disminución de la respuesta miocárdica al isoproterenol tanto in vivo como in vitro, sin observarse modificaciones en el colágeno intersticial. Conclusiones En nuestras condiciones experimentales, el protocolo de natación, con características de ejercicio intenso, produjo una hipertrofia cardíaca moderada con características mixtas de hipertrofia adaptativa y no adaptativa. Si bien la función basal se mantuvo conservada y no hubo cambios en el colágeno intersticial, se observó una disminución en la reserva inotrópica, cronotrópica y lusitrópica.

Mild to moderate exercise reduces cardiovascular risk factors, improves pre-existing pathologic conditions and develops adaptive cardiac hypertrophy. However, the myocardial response to strenuous exercise is scarcely known. Objective The aim of this study was to evaluate baseline ventricular function and myocardial reserve (inotropic, chronotropic and lusitropic response to the ß-adrenergic agonist isoproterenol) in vivo and in vitro in mice following strenuous exercise. Methods Adult male FVB mice (3 months old) were used. The protocol exercise consisted in 90 min swimming sessions twice a day, 6 days/week for 4 weeks. Two experimental groups were evaluated: 1) sedentary group, with no exercise; and 2) exercise group, with full strenuous swimming protocol. Results At the end of the protocol, left ventricular mass increased by 27.9±4% with preserved baseline left ventricular function. In vivo and in vitro myocardial response to isoproterenol decreased with no changes in interstitial collagen. Conclusions Under our experimental conditions, a strenuous swimming protocol produced moderate cardiac hypertrophy with adaptive and maladaptive hypertrophic characteristics. Although baseline ventricular function was preserved with no changes in interstitial collagen, inotropic, chronotropic and lusitropic reserve decreased.

Efectos del ejercicio intenso sobre la función ventricular basal y la respuesta inotrópica, cronotrópica y lusitrópica en ratones / Effects of Strenuous Exercise on Baseline Ventricular Function and Inotropic, Chronotropic and Lusitropic Response in Mice

Introducción El ejercicio leve a moderado reduce los factores de riesgo cardiovascular, mejora estados patológicos previamente establecidos y produce el desarrollo de hipertrofia cardíaca adaptativa. Sin embargo, la respuesta del miocardio frente a un tipo de ejercicio intenso no es del todo conocida. Objetivo Estudiar la función ventricular basal y la reserva miocárdica (respuesta inotrópica, cronotró-pica y lusitrópica frente a un agonista ß-adrenérgico como el isoproterenol) luego de un tipo de ejercicio intenso tanto in vivo como in vitro en ratones. Material y métodos Se utilizaron ratones macho de tres meses de edad de la cepa FVB. El protocolo de ejercicio consistió en dos sesiones diarias de 90 minutos de natación, 6 días/semana durante 4 semanas. Se conformaron dos grupos experimentales: 1) Sedentario: no realiza ejercicio y 2) Ejercicio: realiza protocolo completo de natación intenso. Resultados Al finalizar el protocolo hubo un incremento de la masa ventricular izquierda del 27,9% ± 4%, con función ventricular basal conservada. Sin embargo, hubo una disminución de la respuesta miocárdica al isoproterenol tanto in vivo como in vitro, sin observarse modificaciones en el colágeno intersticial. Conclusiones En nuestras condiciones experimentales, el protocolo de natación, con características de ejercicio intenso, produjo una hipertrofia cardíaca moderada con características mixtas de hipertrofia adaptativa y no adaptativa. Si bien la función basal se mantuvo conservada y no hubo cambios en el colágeno intersticial, se observó una disminución en la reserva inotrópica, cronotrópica y lusitrópica.(AU)

Mild to moderate exercise reduces cardiovascular risk factors, improves pre-existing pathologic conditions and develops adaptive cardiac hypertrophy. However, the myocardial response to strenuous exercise is scarcely known. Objective The aim of this study was to evaluate baseline ventricular function and myocardial reserve (inotropic, chronotropic and lusitropic response to the ß-adrenergic agonist isoproterenol) in vivo and in vitro in mice following strenuous exercise. Methods Adult male FVB mice (3 months old) were used. The protocol exercise consisted in 90 min swimming sessions twice a day, 6 days/week for 4 weeks. Two experimental groups were evaluated: 1) sedentary group, with no exercise; and 2) exercise group, with full strenuous swimming protocol. Results At the end of the protocol, left ventricular mass increased by 27.9±4% with preserved baseline left ventricular function. In vivo and in vitro myocardial response to isoproterenol decreased with no changes in interstitial collagen. Conclusions Under our experimental conditions, a strenuous swimming protocol produced moderate cardiac hypertrophy with adaptive and maladaptive hypertrophic characteristics. Although baseline ventricular function was preserved with no changes in interstitial collagen, inotropic, chronotropic and lusitropic reserve decreased.(AU)

Effect of early versus late AT(1) receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits.

To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg.kg(-1).day(-1)) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT(1)R expression increased in the MI zone at 15 and 35 days (P < 0.05). ANG II levels increased (P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 +/- 0.05 to 3.05 +/- 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 +/- 0.05 to 1.48 +/- 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 +/- 2.35% and MI + losartan: 57.50 +/- 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 +/- 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 +/- 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 0.05). Consequently, the temporal expressions of cardiac AT(1)R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.

Effects of overexpansion on stents' recoil, symmetry/asymmetry, and neointimal hyperplasia in aortas of hypercholesterolemic rabbits.

BACKGROUND: It is not known whether overexpansion modifies stent recoil, symmetric distribution of struts, and neointimal hyperplasia. OBJECTIVES: The objectives were (a) to evaluate whether stent overexpansion modifies the geometric configuration of the stent in the arterial wall, (b) to determine the relationship between overexpansion and stent recoil, and (c) to evaluate the relationship between the distribution of struts and neointimal hyperplasia. METHODS: Twenty tubular stainless steel 316L stents (3.0 and 3.5 mm in diameter) were implanted at 20 and 10 atm, respectively, in the abdominal aorta of New Zealand rabbits fed a hypercholesterolemic diet (1% cholesterol). Sham operations were also performed in seven animals. Eight weeks after implantation or sham operation, an intravascular ultrasound (IVUS) study was performed to measure stent recoil and aid in stent classification (symmetric or asymmetric) according to strut distribution. The degree of injury and neointimal hyperplasia were also evaluated in hematoxylin-eosin stained sections. RESULTS: The symmetry/asymmetry of stents assessed by IVUS, as well as the neointimal hyperplasia, was similar in both groups. Stent recoil was significantly greater in the 3.0-mm stent (overexpanded) group (0.28+/-0.02 mm), as compared with stent recoil in the 3.5-mm stent group (0.10+/-0.01 mm, P<.05). The neointimal hyperplasia in histological slices, independent of the implant technique, was predominantly in zones with higher strut concentration as compared with zones with fewer struts. CONCLUSIONS: Stent overexpansion enhanced stent recoil and did not modify symmetric and asymmetric strut distribution. Neointimal hyperplasia was not modified by the implant technique. Interestingly, significant hyperplasia was observed in locations with greater strut concentration, independent of overexpansion.