RESUMEN
BACKGROUND: Cardiomyocyte apoptosis might contribute to left ventricular (LV) dysfunction following cardiac surgery. Magnetic resonance imaging is considered the most accurate method of determining LV function. We compared apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, TUNEL, staining and detection of caspase 3 activation) and LV function after regional ischemia-reperfusion (I-R) and global cardioplegic ischemia. METHODS: Pigs were randomized to undergo regional myocardial I-R for 20 + 20 min, global myocardial ischemia with cardiopulmonary bypass (CPB) for 40 min or CPB without ischemia (control), followed by 274 min of reperfusion. RESULTS: Compared with the control group, the number of TUNEL-positive cardiomyocytes was higher in the global ischemia group with CPB (0.024 ± 0.014%; p = 0.02) and further increased in areas of unprotected regional I-R (0.444 ± 0.562%; p = 0.003, vs. control). Myocytes with active caspase 3 were detected after global and regional ischemia. The global ejection fraction did not differ between CPB and regional I-R groups. CONCLUSIONS: The use of cardioplegia and CPB efficiently protects the heart from global I-R-induced cardiomyocyte apoptosis during open heart surgery.
Asunto(s)
Apoptosis , Paro Cardíaco Inducido/efectos adversos , Daño por Reperfusión Miocárdica/etiología , Reperfusión Miocárdica/efectos adversos , Miocitos Cardíacos/patología , Animales , Caspasa 3/metabolismo , Hemodinámica , Etiquetado Corte-Fin in Situ , Imagen por Resonancia Magnética , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Distribución Aleatoria , Porcinos , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Acute heart failure is a potentially fatal manifestation of viral myocarditis. Development of myocardial damage in myocarditis involves cardiomyocyte apoptosis. Levosimendan is a novel calcium sensitizing inotropic agent with anti-apoptotic properties. We studied the feasibility of inotropic treatment with levosimendan and its effects on apoptosis in experimental acute heart failure caused by coxsackievirus myocarditis. MATERIALS AND METHODS: Adolescent BALB/c mice were infected with myocarditic Woodruff variant of coxsackievirus B3 (2 x 10(4) plaque-forming units). Mice were randomized into those receiving levosimendan 0.33 mg kg(-1) (total dose 1 mg kg(-1) day(-1)) (n = 20) or vehicle (n = 19) given orally by gauge three times a day for 7 days after infection. Left ventricular function was evaluated by transthoracic echocardiography and the mice were euthanized on day 7. Histopathology, amount of virus in the heart (virus titration assay) and cardiomyocyte apoptosis (TUNEL assay) were studied. Uninfected untreated control mice were also studied. RESULTS: Infection resulted in histopathologically severe myocarditis and significant impairment of left ventricular function. Levosimendan treatment significantly improved ventricular function (fractional shortening 0.32 +/- 0.04 vs. 0.23 +/- 0.05, P = 0.005; contractility 0.60 +/- 0.12 vs. 0.39 +/- 0.14, P = 0.007 and myocardial performance index 0.36 +/- 0.06 vs. 0.62 +/- 0.15, P < 0.0001) compared with vehicle. Levosimendan also reduced cardiomyocyte apoptosis (0.26 +/- 0.08% vs. 0.44 +/- 0.15% in vehicle, P = 0.008), but did not have an effect on areas of myocardial necrosis or inflammation, or the amount of virus in the heart. Levosimendan treatment did not affect mortality (total mortality 63%). CONCLUSIONS; Levosimendan improves ventricular function and inhibits cardiomyocyte apoptosis; therefore, it is suggested as a potentially feasible therapy in acute heart failure caused by viral myocarditis.
Asunto(s)
Cardiotónicos/farmacología , Infecciones por Coxsackievirus/patología , Insuficiencia Cardíaca/patología , Hidrazonas/farmacología , Miocarditis/patología , Miocardio/patología , Piridazinas/farmacología , Animales , Infecciones por Coxsackievirus/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Miocarditis/tratamiento farmacológico , Miocarditis/virología , Miocitos Cardíacos/patología , Simendán , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: Autoantibodies against various endogenous proteins are found in myocarditis. Troponin autoantibodies are detected in patients with chronic dilated cardiomyopathy, but their presence in myocarditis remains unknown. We set out to study the presence of troponin autoantibodies in experimental viral myocarditis. MATERIALS AND METHODS: BALB/c mice infected with coxsackievirus B3 Nancy strain were followed-up at days 1-7 and 2, 4, 8 and 12 weeks after infection. Levels of circulating cardiac troponin I and circulating troponin autoantibodies were measured. Transthoracic echocardiography was performed. Myocarditis was histopathologically graded and cardiomyocyte apoptosis was quantified (TUNEL). RESULTS: Histopathologically relatively mild acute myocarditis followed by persistent cardiomyocyte damage was observed. Rate of cardiomyocyte apoptosis was the highest on day 5 (0.16 +/- 0.01% vs. 0.03 +/- 0.01% in controls, P < 0.001). Circulating troponin I levels were increased to day 5 (45.2 +/- 6.5 ng mL(-1), P < 0.005 vs. controls). Troponin autoantibodies were detected from 2 weeks after infection (20% of animals had autoantibodies at 2 weeks, 60% at 4 and 8 weeks and 20% at 12 weeks, P < 0.05 vs. controls). Fractional shortening remained decreased after acute myocarditis (0.36 +/- 0.02 at 4 weeks, 0.30 +/- 0.02 at 8 and 12 weeks vs. 0.41 +/- 0.01 before infection, P < 0.01) parallel to development of troponin autoantibodies. CONCLUSION: Troponin autoantibodies are formed in experimental virus induced myocarditis following troponin I release and cardiomyocyte apoptosis. The definite role of these autoantibodies remains to be further characterized.
