Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy.

The critical importance of dystrophin to cardiomyocyte contraction and sarcolemmal and myofibers integrity, led us to test the hypothesis that dystrophin reduction/loss could be involved in the pathogenesis of doxorubicin-induced cardiomyopathy, in order to determine a possible specific structural culprit behind heart failure. Rats received total cumulative doses of doxorubicin during 2 weeks: 3.75, 7.5, and 15 mg/kg. Controls rats received saline. Fourteen days after the last injection, hearts were collected for light and electron microscopy, immunofluorescence and western blot. The cardiac function was evaluated 7 and 14 days after drug or saline. Additionally, dantrolene (5 mg/kg), a calcium-blocking agent that binds to cardiac ryanodine receptors, was administered to controls and doxorubicin-treated rats (15 mg/kg). This study offers novel and mechanistic data to clarify molecular events that occur in the myocardium in doxorubicin-induced chronic cardiomyopathy. Doxorubicin led to a marked reduction/loss in dystrophin membrane localization in cardiomyocytes and left ventricular dysfunction, which might constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of doxorubicin-induced cardiac depression. Moreover, increased sarcolemmal permeability suggests functional impairment of the dystrophin-glycoprotein complex in cardiac myofibers and/or oxidative damage. Increased expression of calpain, a calcium-dependent protease, was markedly increased in cardiomyocytes of doxorubicin-treated rats. Dantrolene improved survival rate and preserved myocardial dystrophin, calpain levels and cardiac function, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, mainly regarding specific calpain inhibitors, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy.

Left ventricular global performance and diastolic function in indeterminate and cardiac forms of Chagas' disease.

The majority of patients with Chagas' disease remain for 10 to 30 years in the indeterminate form (IF) of this disease. They have no symptoms, serologic positivity, normal electrocardiogram results and heart size, and normal left ventricular global and segmental systolic function on 2-dimensional echocardiography. To investigate whether this group of patients have any impairment of left ventricular global performance (Tei index) and diastolic function, we have studied 43 individuals (age 49 +/- 12 years) including 14 healthy volunteers and 29 patients with Chagas' disease divided as IF (n = 12) and cardiac form (n = 17). Echocardiographic measurements included ejection fraction, Tei index, left atrial volume index, transmitral (peak early transmitral flow velocity, late peak mitral velocity, tissue Doppler, late peak mitral velocity duration) and pulmonary (systolic pulmonary vein velocity, diastolic pulmonary vein velocity, retrograde pulmonary vein velocity, retrograde pulmonary vein velocity duration) flow velocities, and tissue Doppler velocities at lateral mitral annulus (peak early transmitral flow velocity, late peak mitral velocity, systolic pulmonary vein velocity). Although ejection fraction and S' velocity were significantly lower for patients with cardiac form compared with control and IF groups, Tei index was not able to differentiate patients with cardiac conditions from the other groups. Diastolic dysfunction was documented for patients with cardiac form by left atrial volume index, early transmitral peak velocity, early expansion wave by tissue Doppler, late expansion wave by tissue Doppler, and peak early transmitral flow velocity/early expansion wave by tissue Doppler. Patients with the IF of Chagas' disease did not show any abnormality of diastolic function. Thus, when the IF is further characterized on the basis of absence of any echocardiographic marker of regional systolic dysfunction, no impairment of diastolic function can be detected.