Effect of direct-acting antivirals on corrected QT interval and cardiac functions in patients with chronic hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is a major public health problem in Egypt. The use of direct-acting antivirals (DAAs) in such patients has been shown to be highly effective. The cardiac safety of such antivirals remains uncertain. This study aimed to assess the effect of the novel DAAs on corrected QT (QTc) interval and on cardiac function using trans-thoracic echocardiography. RESULTS: This was a prospective cohort study performed on 100 patients suffering from chronic HCV infection. Patients were into two equal groups according to the presence of liver cirrhosis. The group without liver cirrhosis received a daily combination of sofosbuvir 400 mg and daclatasvir 60 mg for 12 weeks while that with liver cirrhosis (Child-Pugh score A or B) received a daily combination of sofosbuvir 400 mg, daclatasvir 60 mg, and ribavirin 600 mg for 12 weeks. Surface ECG and trans-thoracic echocardiography were performed prior to the start of treatment and after 12 weeks of treatment. At the end of treatment, no changes were observed in QTc interval in those with (p = 0.48) or without (p = 0.048) liver cirrhosis. In patients without liver cirrhosis, right ventricular global longitudinal strain (RV GLS) decreased from 22 (-30 to -17) to -21 (-27-18), p = 0.024. In patients with liver cirrhosis, lateral mitral E' velocity was reduced from 14.38 ± 3.59 to 13.62 ± 3.21 cm/s, p = 0.02 and indexed left atrial volume (LAVI) was increased from 25.96 ± 3.96 to 26.86 ± 4.12 ml/m2, p = 0.032. There were no changes in both groups regarding left ventricular (LV) dimensions, ejection fraction, trans-mitral E/A ratio, E/E' ratio, deceleration time, right ventricular (RV) systolic pressure, mean pulmonary artery pressure, RV fractional area change, tricuspid annular plane systolic excursion, and LV GLS. CONCLUSION: The current national protocol of HCV infection treatment with direct-acting antiviral agents used in Egyptian patients has a good cardiac safety profile. Such treatments have no effect on QTc interval, left and right ventricular functions except for a decrease in RV GLS in those with no liver cirrhosis and a reduction in lateral mitral E' velocity in those with liver cirrhosis both remained within the normal reference range.

Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFß1) in myofibroblastic metaplasia.

PURPOSE: Superficial peritoneal endometriotic (pEM) lesions are composed of endometrial glands and stroma, in addition to a third component-myofibroblasts and smooth muscles (SM)-like cells. The latter develops secondary to a metaplasia. In this study, we characterised the third component cells in pEM according to differentiation markers in different micro-compartments. Furthermore, a possible effect of TGFß1 on myofibroblastic metaplasia in endometriotic epithelial cells was studied. METHODS: Seventy-six premenopausal patients were included. Peritoneal biopsies were excised from EM patients (n = 23), unaffected peritoneum (peritoneum from EM patients but without EM components, n = 5/23) and non-EM patients (n = 10). All peritoneal biopsies were immunolabeled for ASMA, calponin, collagen I, desmin, TGFß receptor 1 (R1), R2 and R3 in addition to ultrastructure examination by transmission electron microscopy (TEM) (n = 1). TGFß1 level was measured in peritoneal fluid (PF) (EM, n = 19 and non-EM, n = 13) collected during laparoscopy. Furthermore, TGFß1 effect on myofibroblastic metaplasia was studied in vitro. RESULTS: At the centre of pEM lesions, calponin immunolabeling outweighs the collagen I while in the periphery the reverse occurs. SM-like cells expressing desmin predominate at the periphery, while ASMA immunolabeling was detectable in all micro-compartments. Both indicate an abundance of myofibroblasts at the centre of pEM lesions and SM-like cells in the periphery. Although activated TGFß1 in PF did not differ between EM and non-EM, it inhibited the cell proliferation of the endometriotic epithelial cells and induced an upregulation in ASMA and collagen IA2 expression as well. CONCLUSION: The abundance of the myofibroblasts and SM-like cells points to a myofibroblastic metaplasia in pEM. Both cells are differentially arranged in the different micro-compartments of pEM lesions, with increasing cell maturity towards the periphery of the lesion. Furthermore, TGFß1 may play a role in the myofibroblastic metaplasia of the endometriotic epithelial cells. These findings provide a better insight in the micro-milieu in EM lesions, where most of the disease dynamics occur.

Myofibroblasts Are Evidence of Chronic Tissue Microtrauma at the Endometrial-Myometrial Junctional Zone in Uteri With Adenomyosis.

BACKGROUND: Adenomyosis (AM) uteri exhibit hyperperistalsis. The latter causes a chronic tissue trauma at the endometrial-myometrial junctional zone (EMJZ). Upon tissue trauma, microdehiscences in the myometrium facilitate the translocation of basal endometrial fragments into the myometrium. There, a metaplasia (mediated by transforming growth factor ß1 [TGFß1] and connective tissue growth factor [CTGF]) occurs and AM lesions develop. The abundance of myofibroblasts in a tissue hallmarks metaplasia and points to a tissue microtrauma. MATERIALS AND METHODS: To study if myofibroblasts-as an evidence of tissue microtrauma-are more abundant at EMJZ in AM-uteri, a case-control experimental study was carried out at Charité University Hospital-Endometriosis Research Centre. In all, 18 uteri with AM and 14 uteri without AM were obtained during laparoscopy-assisted vaginal hysterectomy. The immunolabeling of myofibroblastic metaplasia (alpha smooth muscle actin [ASMA] and collagen I), differentiated smooth muscle marker (desmin) and metaplasia mediators (TGF-ß receptors 1, 2, 3 and CTGF) was investigated. The ultrastructure of myofibroblasts at EMJZ of AM uterus was characterized by transmission electron microscopy, in addition to an in vitro study to characterize myofibroblasts in the endometrium of non-AM uterus. RESULTS: Immunolabeling of ASMA and collagen I was significantly higher at EMJZ of AM uteri versus non-AM uteri. Furthermore, myofibroblasts were ultrastructurally characterized at EMJZ of AM. Endometrium of non-AM uterus exhibited 5% to 8% of its cells, expressing ASMA and collagen I. No difference was noted regarding metaplasia mediators immunolabeling between both the groups. CONCLUSION: The abundant and persistent myofibroblasts (expressing ASMA/collagen I) at EMJZ in AM uteri are ultra-/microscopic evidence of chronic tissue trauma. They are of nonmyometrial origin, as they lack desmin immunolabeling.

Abdominal Wall Endometriosis: Myofibroblasts as a Possible Evidence of Metaplasia: A Case Report.

In this study, we report about a patient with extra-uterine endometriosis (EM) in the abdominal wall muscle with evident metaplasia based on the abundant alpha smooth muscle actin (ASMA)-expressing myofibroblasts. Laparotomy excision of the abdominal wall EM was done following ultrasonographic evidence of a hypodense swelling in the right rectus abdominis, which was confirmed by MRI. Immunohistochemistry staining for ASMA and collagen I was done, with the results confirming that endometriotic stromal cells expressed both. Anterior abdominal wall endometriosis was suspected because of the patient's history of recurrent EM combined with the cyclic nature of symptoms. MRI is useful in determining the extent of the disease. In case of persisting symptoms even under hormonal treatment, surgical excision is mandatory. The expression of both ASMA and collagen I in and around EM lesions supports the notion of the metaplastic process in the course of disease development.