RESUMEN
Background: Reverse remodeling is a clinically relevant endpoint in heart failure with reduced ejection fraction (HFrEF). Rho-kinase (ROCK) signaling cascade activation correlates with cardiac remodeling and left ventricular (LV) systolic dysfunction in HFrEF patients. Cardiac resynchronization therapy (CRT) is effective in HFrEF, especially when there is a left bundle block, as this treatment may stimulate reverse remodeling, thereby improving quality of life and prolonging survival for patients with this severe condition. Here, we evaluate the hypothesis that ROCK activation is reduced after effective CRT in HFrEF. Methods: ROCK activation in circulating leukocytes was evaluated in 28 HFrHF patients, using Western blot (myosin light chain phosphatase subunit 1 phosphorylation, MYPT1p/t), before and three months after initiation of CRT. LV systolic function and remodeling were assessed by echocardiography. Results: Three months after CRT, LV ejection fraction increased an average of 14.5% (p < 0.001) in 13 patients (responders), while no change was observed in 15 patients (non-responders). End-systolic diameter decreased 16% (p < 0.001) in responders, with no change in non-responders. ROCK activation in PBMCs decreased 66% in responders (p < 0.05) but increased 10% in non-responders (NS). LV end-diastolic diameter was also 5.2 mm larger in non-responders vs. responders (p = 0.058). LV ejection fraction, systolic diameter, and ROCK activation levels were similar in both groups at baseline. Conclusion: In HFrEF patients, 3 months of effective CRT induced reverse myocardial remodeling, and ROCK activation was significantly decreased in circulating leukocytes. Thus, decreased ROCK activation in circulating leukocytes may reflect reverse cardiac remodeling in patients with heart failure.
RESUMEN
INTRODUCCIÓN: Los ratones SR-B1 KO/ApoER6 1h/h que son alimentados con una dieta rica en grasas saturadas, desarrollan enfermedad coronaria aterosclerótica severa, complicaciones isquémicas e insuficiencia cardíaca, con alta mortalidad. Los estudios con este modelo se han enfocado fundamentalmente en la enfermedad coronaria y menos en el remodelado cardíaco. El OBJETIVO del trabajo ha sido caracterizar el remodelado miocárdico, evaluar la evolución temporal de la función ventricular izquierda y la sobrevida asociada a enfermedad cardíaca por ateromatosis. MÉTODO: Ratones homocigotos SR-B1 KO/ApoER6 1h/h fueron alimentados por 8 semanas con dieta aterogénica o dieta normal y se comparó la sobrevida en ambos grupos. A las 4 semanas se realizó un ecocardiograma bidimensional. En los ratones eutanasiados se evaluó en la pared cardíaca fibrosis miocárdica y tamaño de los cardiomiocitos por morfometría, apoptosis con técnica de TUNEL e infiltración por células inflamatorias mononucleares (ED1) por inmunohistoquímica. RESULTADOS: En el grupo que recibió dieta aterogénica la sobrevida se redujo en 46,7% (p < 0.001), debido a muerte súbita y a falla cardíaca progresiva. En este grupo, a las 4 semanas se observó dilatación de cavidades izquierdas y disminución de la fracción de eyección del ventrículo izquierdo en comparación con el grupo control (79,3 ± 1,3% vs 66 ± 3,7%, p<0,01). También se observó aumento de la masa cardíaca relativa de 2.1 veces (p<0,001) y del peso pulmonar relativo en 80% (p<0,001), sin cambios en las dimensiones de los cardiomiocitos. En el miocardio de los ratones que recibieron dieta aterogénica hubo un aumento de la fibrosis cardíaca de 7.9 veces (p < 0.01) y del número de cardiomiocitos apoptóticos en 55.9 veces (p < 0.01), junto a un aumento del número de células inflamatorias mononucleares ED1. CONCLUSIONES: En el modelo de falla cardíaca severa de etiología isquémica con alta mortalidad en el ratón homocigoto SR-B1 KO/ApoER6 1h/h sometido a una dieta aterogénica, con falla cardíaca izquierda por disfunción sistólica, el remodelado patológico del miocardio está dado fundamentalmente por apoptosis y fibrosis. También se observa un aumento discreto de macrófagos en la pared cardíaca. Es posible que el edema parietal también pueda ser un mecanismo de remodelado relevante en este modelo.
Abstract: SR-B1 KO/ApoER6 1h/h mice fed a high saturated fat diet develop severe coronary atheromatosis, and cardiac failure with a high mortality rate. Cardiac remodeling under these conditions has not been well studied. AIM: To evaluate the time course of left ventricular function, cardiac remodeling and survival associated to the administration of an atherogenic diet. METHOD: Homozygote SR-B1 KO/ApoER6 1h/h mice received an atherogenic diet for 8 weeks. Mice receiving a normal diet served as controls. Survival rate, myocardial fibrosis, cardiomyocyte size, apoptosis and infiltration by inflammatory or mononuclear cells were compared between groups. A TUNEL technique was used to evaluate apoptosis. RESULTS: A 46.7% survival reduction compared to controls was observed in the experimental group (p<0.01), due to left ventricular and atrial dilatation associated to a decrease in ejection fraction (79,3 ± 1,3% vs 66 ± 3,7%, p<0,01, respectively). Also, an increased cardiac weight, 2.6 times greater was observed in the experimental group, compared to controls. Mice receiving the atherogenic diet showed an 80% increased lung weight. There was no evident change in cardiomyocytes, but there was more (7.9 times) cardiac fibrosis (p<0.01) and 55.9 times more apoptotic cells. (p<0.01), along with a greater number of inflammatory cells and ED1 mononuclear cells. CONCLUSION: Mice receiving an atherogenic diet develop heart failure and reduced survival rate. This is associated with cardiac remodeling with underlying apoptosis an ventricular wall fibrosis. It is posible that wall edema might contribute to the observed cardiac remodeling.
