Subclinical Myocardial Impairment Occurred in Septal and Anterior LV Wall Segments After Anthracycline-Embedded Chemotherapy and did not Worsen During Adjuvant Trastuzumab Treatment in Breast Cancer Patients.

In a previous study of breast cancer patients, we found changes in cardiac function and size during the early stages of adjuvant trastuzumab (Herceptin(®)) therapy. Here we present a subgroup analysis of this patient cohort. This subgroup received a anthracycline-embedded chemotherapy followed by at least 3 months up to 6 months of adjuvant Herceptin(®) therapy. Twenty-seven female breast cancer patients with Her-2/-neu overexpression were studied using conventional echocardiography and 2D speckle tracking. These methods were done before anthracycline-embedded chemotherapy, before adjuvant trastuzumab therapy, and both 3 and 6 months after the start of the therapy (T3, T6). The LV-EF (Simpson biplane) decreased significantly from before the chemotherapy to after the chemotherapy and further decreased after 3 months of trastuzumab therapy (66.2 ± 1.5 vs. 58.7 ± 1.2 vs. 55.6 ± 1.3 vs. 55.9 ± 1.5 %; p < 0.05). The stroke volume index remained constant after chemotherapy (22.0 ± 0.8 vs. 22.6 ± 1.3 ml/m(2); p = 0.9), but increased significantly during trastuzumab therapy (26.7 ± 1.1 and 27.3 ± 1.0 ml/m(2); p < 0.01). Global longitudinal strain exclusively decreased during chemotherapy (-21.0 ± 0.5 vs. -18.9 ± 0.5 %, p < 0.001). Regional longitudinal strain decreased significantly after chemotherapy in septal, anteroseptal, anterolateral, and apex segments. Mitral valve regurgitation increased during the whole treatment, but especially during trastuzumab. Right ventricular function decreased exclusively during chemotherapy. Anthracycline-embedded chemotherapy in patients with breast cancer led to a decrease in LV function, especially of the septal and anterior segments, and did not worsen during adjuvant trastuzumab treatment.

In situ postconditioning with neuregulin-1ß is mediated by a PI3K/Akt-dependent pathway.

BACKGROUND: The myocardial infarct size can be reduced by pharmacological postconditioning using cardioprotective agents. Neuregulin-1ß is a potential candidate, but previous studies in an isolated heart model of ischemia and reperfusion displayed controversial results. An in situ model of ischemia/reperfusion was used to clarify whether the remote application of neuregulin-1ß can reduce the reperfusion injury. A second aim was to evaluate, if the effects are specific for reperfused tissue or if this is a general antiapoptotic effect. In addition, the contributing molecular mechanisms were investigated. METHODS: In an open chest model, mouse hearts were subjected to a regional ischemia (45-minute) using ligature of the left anterior descending artery. Neuregulin-1ß (80 ng/kg) was given using an intraperitoneal bolus injection 5 minutes before reopening of the ligature followed by a 30-minute reperfusion. RESULTS: Remote application of recombinant neuregulin-1ß protected the heart from reperfusion injury without influencing hemodynamics. This beneficial effect specifically targets reperfusion injury. In contrast, nonreperfused needle trauma was not reduced by neuregulin-1ß when applied remotely. Pharmacological blocking experiments and enzyme activation analysis using Western blot analysis revealed a crucial involvement of the antiapoptotic reperfusion injury salvage kinase cascade. In contrast, contribution of the survivor activating factor enhancement pathways to this early cardioprotection was not observed. CONCLUSIONS: Remote application of neuregulin-1ß protects hearts from early reperfusion injury by activation of the reperfusion injury salvage kinase pathway without relevant effects on intracardiac pressures in myocardial infarction. Besides its potential pharmacological application, neuregulin-1ß might act as an endogenously produced mediator in remote postconditioning.

Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy.

OBJECTIVE: Recent studies in breast cancer patients and Trastuzumab therapy (Herceptin) showed a development of a toxic cardiomyopathy as a severe complication. The aim of this study was to discover early changes in cardiac function and morphology. METHODS: We studied 42 female patients with Her-2/-neu over-expression in breast cancer by echocardiography before, 3, and 6 months after start of the adjuvant Herceptin therapy. All values were mean value ± standard deviation. RESULTS: After 3 or 6 months of a trastuzumab therapy we discovered significant increases in the diastolic and systolic left ventricle volume indices (LV-DVI 32.4 ± 8.5 vs. 38.5 ± 8.7 vs. 40.3 ± 10.3 ml/m², p < 0.001 and LV-SVI 12.6 ± 4.0 vs. 15.7 ± 4.7 vs. 17.2 ± 6.8 ml/m², p < 0.001), an increase of the end-diastolic and end-systolic LV diameter (LVEDD 46.8 ± 4.2 vs. 48.0 ± 4.7 vs. 49.7 ± 4.5 ml/m², p < 0.01; LVESD 28.3 ± 4.2 vs. 31.0 ± 4.7 vs. 32.3 ± 4.9 mm, p < 0.001), a reduced systolic ventricle function determined by the tissue Doppler imaging (TDI) velocity (9.2 ± 2.5 vs. 8.0 ± 1,7 vs. 7.7 ± 1.5 cm/s, p < 0.001), fractional shortening (39,6 ± 7.5 vs. 35.4 ± 7.4 vs. 35.2 ± 7.0%, p < 0.01), and the LV-EF Simpson biplane [62.0 ± 5.1 vs. 60.1 ± 6.3 (p = ns) vs. 58.4 ± 7.9%, p < 0.01] compared to pretreatment values. There was also an increase of the left atrial volume index (21.4 ± 6.2 vs. 26.2 ± 7.9 vs. 29.7 ± 8.8 ml/m², p < 0.001), a decrease of the median TDI atrial velocities (11.9 ± 2.4 vs. 10.5 ± 2.8 vs. 10.1 ± 2.1 cm/s, p < 0.01), an increase of the peak early diastolic filling velocities (73.1 ± 15.4 vs. 83.1 ± 16.4 vs. 82.2 ± 19.4 cm/s, p < 0.05), and an increase of the median mitral valve insufficiency degree (0.64 ± 0.65 vs. 1.03 ± 0.76 vs. 1.11 ± 0.73°, p < 0.001). We could not detect a significant increase in diastolic dysfunction. Also right heart diameters and function did not change significantly. Most patients stayed in an asymptomatic stage of cardiac disease. CONCLUSION: The blockade of Her2/-neu receptors with trastuzumab in patients with breast cancer led to measurable alterations of left ventricular volume, left atrial volume, and systolic function as early as 3 months after start of treatment.

Isolated rupture of the right upper pulmonary vein: a blunt cardiac trauma case.

A 37-year-old woman who sustained blunt chest trauma as a result of a car accident was found unconscious at the accident site with signs of circulatory compromise. Computed tomographic trauma screening excluded thoracic, intracranial, and intra-abdominal bleeding, or other pathologic findings, except a small circumferential hemopericardium. Echocardiography revealed a hemopericardium that was partially clotted and the beginning of compression of the right ventricle. Because of progressive hemodynamic compromise, the decision was made for operative exploration. After a median sternotomy, the resultant excessive bleeding necessitated extracorporeal circulation. Careful inspection revealed isolated rupture of the upper right pulmonary vein, which was successfully repaired.

Early assessment of pulmonary inflammation by 19F MRI in vivo.

BACKGROUND: Emulsified perfluorocarbons (PFCs) are preferentially phagocytized by monocytes/macrophages and are readily detected by (19)F MRI. This study tests the hypothesis that (19)F MRI can be used to quantitate pulmonary inflammation by tracking of infiltrating PFC-loaded monocytes. METHODS AND RESULTS: Pneumonia was induced in mice by intratracheal instillation of lipopolysaccharides (LPS) followed by intravenous injection of PFCs. Whereas regular (1)H MRI provided no evidence of lung injury 24 hours after LPS, the concurrent (19)F images clearly show PFC accumulation in both pulmonary lobes. Imaging at 48 hours after LPS revealed signals in (1)H images at the same location as the 24-hour (19)F signals. Thus, progressive pneumonia was first predicted by (19)F MRI early after PFC administration. Without LPS, at no time were (19)F signals observed within the lung. Histology and fluorescence-activated cell sorting (FACS) combined with (19)F MRI confirmed the presence of infiltrating PFC-loaded monocytes/macrophages after LPS challenge. Additional experiments with graded doses of LPS demonstrated that (19)F signal intensity strongly correlated with both LPS dose and pathological markers of lung inflammation. In separate studies, dexamethasone and CGS21680 (adenosine 2A receptor agonist) were used to demonstrate the ability of (19)F MRI to monitor anti-inflammatory therapies. CONCLUSIONS: PFCs serve as a contrast agent for the prognostic and quantitative assessment of pulmonary inflammation by in vivo (19)F MRI, which is characterized by a high degree of specificity due to the lack of any (19)F background. Because PFCs are biochemically inert, this approach may also be suitable for human applications.