To Alfred Deakin

To access publisher full text version of this article. Please click on the hyperlink in Additional Link fieldOBJECTIVE: Anthracyclines (AC) have contributed significantly to increased survival rate in acute lymphoblastic leukemia (ALL), although the use of these drugs is limited due to cardiotoxicity. The aim was to evaluate heart muscle function in asymptomatic adult survivors of ALL treated in early childhood in relation to the combined effects of AC and other potential cardiotoxic factors. PROCEDURE: Twenty-three young adult ALL survivors who had all received treatment with median 120 (120-400) mg AC/m(2) before the onset of puberty were examined median 21 years after remission and compared with 12 healthy controls. Basal echocardiography including two-dimensional (2D) M-mode and Doppler examination was performed, followed by a maximal exercise stress test and stress echocardiography immediately after stress test and after 5 min recovery. RESULTS: We found significant differences in systolic function between patients and controls at maximal exercise despite absence of reported symptoms from the patients. The most marked difference was in ejection fraction at stress 59.5% (32.6-81.1) and 77.3% (66.2-85.3), respectively (P < 0.00006). Ten out of 23 patients reduced their ejection fraction at stress compared with at rest; this was not found in any of the controls. Cardiovascular risk factors such as GH deficiency and a high proportion of trunk fat did not have an impact on cardiac function. CONCLUSIONS: With very long follow up in a homogenous cohort of ALL survivors, we found subclinical cardiac dysfunction with exercise stress echocardiography even after low doses of AC

Induction of cardiomyopathy in severe combined immunodeficiency mice by transfer of lymphocytes from patients with idiopathic dilated cardiomyopathy

Growing evidence suggests that autoimmune mechanisms play an important role in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). The aim of the study was to evaluate the effects of transfer of lymphocytes from patients with DCM into severe combined immunodeficiency (SCID) mice on the heart structure and function. Thirty CB-17 SCID (6-8 weeks old) mice were used and divided into 3 groups (n=10). Mice were injected intraperitoneally with up to 25 x 10 peripheral blood lymphocytes (PBL) from either patients with DCM which contain human autoantibodies against cardiac Pj-adrenergic receptors and M(2)-muscarinic receptors (DCM group) or PBL from healthy controls (control-H group). Ten mice did not receive any injections and were used as baseline controls (control-N group). Echocardiography and morphological studies were performed seventy five days after the transfer. Results showed that in DCM group, left ventricle dimensions (LVD) in diastole were increased (4.2 ± 0.1mm) as compared to both control-H group (3.8 ± 0.1mm) and control-N group (3.6 ± 0.1 mm) (p < 0.01). Further, there was a trend for increased LVD in systole. Fractional shortening was not different between groups. Histological evaluation revealed accumulation of human lymphocytes in the capillaries and scarce infiltration of the lymphocytes in the hearts from DCM group. Diffuse fibrosis was significant increased in DCM mice as compared to mice receiving PBL from normal subjects (2.2 ± 0.3 % vs. 0.8 ± 0.1 %, p < 0.01). In conclusion, transfer of the PBL from the patients with DCM was able to induce early stage of heart dilatation in SCID mice. These data provide for the first time the direct evidence supporting that the autoimmune mechanism is important in the pathogenesis of human DCM

Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene

Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2 ± 2.4 vs. 34.6 ± 3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6 ± 1.6 vs. 2.7 ± 0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25 ± 3.0% vs. 39.9 ± 3.1%; ejection fraction, 57 ± 9 vs. 77 ± 5; mean velocity of circumferential shortening, 4.5 ± 0.8 vs. 7.0 ± 1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3 ± 0.08 vs. 2.1 ± 0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function