scholarly journals GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy

2016 ◽  
Vol 310 (11) ◽  
pp. H1808-H1815 ◽  
Author(s):  
Rasha M. S. M. Mohamed ◽  
Sachio Morimoto ◽  
Islam A. A. E.-H. Ibrahim ◽  
Dong-Yun Zhan ◽  
Cheng-Kun Du ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Glycogen Synthase ◽  
Troponin T ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Myosin Heavy Chain Isoform ◽  
Familial Dilated Cardiomyopathy ◽  
Gsk 3Β

Glycogen synthase kinase-3β (GSK-3β) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3β in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3β (GSK-3β+/− KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3β+/− KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3β+/− KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3β+/− KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.

The effects of dexrazoxane on cardiac status and second malignant neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9503-9503 ◽  
Author(s):  
Lisa M. Kopp ◽  
Mark L. Bernstein ◽  
Cindy L. Schwartz ◽  
David Ebb ◽  
Mark D. Krailo ◽  
...  
Keyword(s):  
Troponin T ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
European Medicines Agency ◽  
Malignant Neoplasms ◽  
Secondary Malignancies ◽  
Her2 Positive ◽  
Pilot Studies ◽  
Second Malignant Neoplasms

9503 Background: Anthracyclines are highly efficacious in OS but associated with risk of cardiotoxicity. We conducted two studies using dexrazoxane as a cardioprotectant: i) AOST0121, a phase II study for metastatic OS and ii) P9754, a series of pilot studies including doxorubicin dose intensification in patients with localized OS. Methods: Patients on AOST0121 received methotrexate, doxorubicin (375 mg/m2), cisplatin, ifosfamide and etoposide (MAPIE). Those with HER2-positive tumors also received trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). On P9754, patients received MAP in Pilot 1, MAPI or MAPIE in Pilots 2 and 3. Total doxorubicin was 450 mg/m2 or 600 mg/m2 with each dose preceded by dexrazoxane (10:1 ratio). Etoposide was never given simultaneously with dexrazoxane. Measurements of left ventricular systolic function by echocardiography, serum troponin-T (cTnT, a myocardial injury marker) and N-terminal pro-brain natriuretic peptide (NT-proBNP, a cardiomyopathy marker) were obtained at baseline and repeated during therapy. Secondary malignancies were reported to the NCI. Results: None of the 47 patients (17 receiving trastuzumab) evaluated for cardiac toxicity on AOST0121 had significant changes in left ventricular fractional shortening, measurable cTnT, elevation of NT-proBNP or clinical evidence of cardiotoxicity (CTCv2.0). In P9754, 242 patients were evaluated for cardiotoxicity. Only 1 patient had CTCv2.0 grade 3 toxicity and 1 patient had a measurable cTnT. Three of 96 patients treated on AOST0121 and two of 272 patients on P9754 developed AML. Combining both studies: 5/398 or 1.4%. Conclusions: This large group of OS patients demonstrates that dexrazoxane is an effective cardioprotectant for doxorubicin alone (375-600 mg/m2), and in combination with trastuzumab. Dexrazoxane did not lead to an increase in secondary malignancies in OS patients treated with these regimens as compared to historical rates of 1-2%. Our results do not support the findings of a recent European Medicines Agency safety review that concluded dexrazoxane was unsafe for use in children and adolescents due to risk of SMN.

scholarly journals Tako-tsubo cardiomyopathy observed in a patient with sepsis and transient hyperthyroidism

2016 ◽  
Vol 72 (1) ◽  
Author(s):  
Filippo M. Sarullo ◽  
Luigi Americo ◽  
Salvatore Accardo ◽  
Sergio Cicero ◽  
Rossella Schicchi ◽  
...  
Keyword(s):  
Troponin T ◽  
Systolic Function ◽  
Significant Coronary Artery Disease ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Blood Analysis ◽  
Thyroid Peroxidase ◽  
Free Triiodothyronine ◽  
Creatine Kinase Mb ◽  
Tako Tsubo Cardiomyopathy

ischemic stroke with residual left hemiparesis, was admitted to our hospital because of dyspnoea with clinical evidence of acute pulmonary edema. She was found to have a sinus tachycardia with ST-elevation in leads D1, aVL and V1-V4 in the electrocardiogram, and akinesis of the left ventricular apex with overall left ventricular systolic function being severely impaired and an ejection fraction of 28% on echocardiography. Orotracheal intubation was performed and mechanical ventilation was immediately started. Emergency cardiac catheterization was performed 2 h after the symptom onset. Coronary angiography showed no significant coronary artery disease. Blood analysis revealed an increase in the creatine kinase MB fraction, a significant positive detection in troponin T, a white blood cell count of 35000 per microliter, C-reactive protein of 59,9 mg/dl, and transient elevation in the concentration of free triiodothyronine, free thyroxine, thyroid globulin antibody, and thyroid peroxidase antibody. The symptoms improved during the next days, and follow-up echocardiography 18 days later showed complete resolution of the left ventricular dysfunction. These data suggest that tako-tsubo cardiomyopathy may be induced in patients with sepsis and transient hyperthyroidism.

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