A Gene Expression Profile of the Myocardial Response to Clenbuterol

Clenbuterol is currently being used as part of a clinical trial into a novel therapeutic approach for the treatment of end-stage heart failure. The purpose of this study was to determine the global pattern of myocardial gene expression in response to clenbuterol and to identify novel targets and pathways involved. Rats were treated with clenbuterol (n = 6) or saline (n = 6) for periods of 1, 3, 9, or 28 days. Rats treated for 28 days were also subject to continuous electrocardiogram analysis using implantable telemetry. RNA was extracted from rats at days 1 and 28 and used from microarray analysis, and further samples from rats at days 1, 3, 9, and 28 were used for analysis by real-time polymerase chain reaction. Clenbuterol treatment induced rapid development of cardiac hypertrophy with increased muscle mass at day 1 and elevated heart rate and QT interval throughout the 28-day period. Microarray analysis revealed a marked but largely transitory change in gene expression with 1,423 genes up-regulated and 964 genes down-regulated at day 1. Up-regulated genes revealed an unexpected association with angiogenesis and integrin-mediated cell adhesion and signaling. Moreover, direct treatment of endothelial cells cultured in vitro resulted in increased cell proliferation and tube formation. Our data show that clenbuterol treatment is associated with rapid cardiac hypertrophy and identify angiogenesis and integrin signaling as novel pathways of clenbuterol action. The data have implications both for our understanding of the physiologic hypertrophy induced by clenbuterol and for treatment of heart failure. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Outcome in adult patients after arterial switch operation for transposition of the great arteries

Background

The arterial switch operation (ASO) is currently the treatment of choice in neonates with transposition of the great arteries (TGA). The outcome in childhood is encouraging but only limited data for long-term outcome into adulthood exist.

Methods and results

We studied 145 adult patients (age > 16, median 25 years) with ASO followed at our institution. Three patients died in adulthood (mortality 2.4/1000-patient-years). Most patients were asymptomatic and had normal left ventricular function. Coronary lesions requiring interventions were rare (3 patients) and in most patients related to previous surgery. There were no acute coronary syndromes. Aortic root dilatation was frequent (56% patients) but rarely significant (> 45 mm in 3 patients, maximal-diameter 49 mm) and appeared not to be progressive. There were no acute aortic events and no patient required elective aortic root surgery. Progressive neo-aortic-valve dysfunction was not observed in our cohort and only 1 patient required neo-aortic-valve replacement. Many patients (42.1%), however, had significant residual lesions or required reintervention in adulthood. Right ventricular outflow tract lesions or dysfunction of the neo-pulmonary-valve were frequent and 8 patients (6%) required neo-pulmonary-valve replacement. Cardiac interventions during childhood (OR 3.0, 95% CI 1.7–5.4, P < 0.0001) were strong predictors of outcome (cardiac intervention/significant residual lesion/death) in adulthood.

Conclusions

Adult patients with previous ASO remain free of acute coronary or aortic complications and have low mortality. However, a large proportion of patients require re-interventions or present with significant right sided lesions. Life-long cardiac follow-up is, therefore, warranted. Periodic noninvasive surveillance for coronary complications appears to be safe in adult ASO patients.     

An Abnormal Dipyridamole Thallium/Sestamibi Fails to Predict Long-term Cardiac Events in Vascular Surgery Patients

Recent data demonstrate that dipyridamole-thallium (DTHAL) and sestamibi (DMIBI) are not predictive of adverse perioperative cardiac events in moderate-risk patients (one or more Eagle risk factors) undergoing major elective vascular surgery. Less data are available regarding the ability of DTHAL/DMIBI to predict adverse cardiac events on long term follow-up. We sought to determine whether an abnormal DTHAL/DMIBI is predictive of adverse cardiac events on long-term follow-up in moderate-risk patients undergoing major elective vascular surgery. Patients were enrolled prospectively between June 1997 and June 1999 at West Los Angeles VA and Harbor-UCLA Medical Centers. Adverse cardiac events were defined as congestive heart failure (CHF), myocardial infarction (MI), unstable angina (USA), and ventricular arrhythmias. Follow-up was obtained via clinic visits, telephone calls, and chart review. We studied 75 patients (76% male, 24% female) with a mean age of 65 years. Operative procedures were primarily femorodistal (83%) and aortic (16%). DTHAL/DMIBI results were normal in 35 patients (47%), demonstrated reversible ischemia in 26 (35%), and showed a fixed defect alone in 14 (18%). From the follow-up results of this study we conclude that there is no association between a reversible ischemia or an abnormal (fixed or reversible) DTHAL/DMIBI and adverse cardiac events or mortality on long-term follow-up in moderate-risk patients who have undergone major vascular surgery.     

Identification of cell-specific soluble mediators and cellular targets during cell therapy for the treatment of heart failure

Cell therapy, the transplantation of progenitor cells into the myocardium, has been proposed as a possible treatment strategy for heart failure. Despite the lack of repopulation of the heart with progenitor cells, cell therapy induces a modest but well-documented functional improvement in patients. It is thought that paracrine mechanisms may account for the observed changes in heart function. However, there is little evidence that directly supports this hypothesis. We discuss the current views in the literature and present some preliminary data proposing that adult progenitor cells influence contractility and Ca2+ handling in neighboring failing cardiomyocytes by soluble mediators. This can be tested using a co-culture system. Our results suggest that soluble mediators from adult progenitor cells can enhance failing cardiomyocyte function, supporting the paracrine hypothesis. This co-culture strategy can be employed to identify cell-specific soluble mediators and their cellular targets during cell therapy for the treatment of heart disease.     

Urinary interleukin 22 binding protein as a marker of lupus nephritis in Egyptian children with juvenile systemic lupus erythematosus

Juvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune inflammatory disease. Generally, 60% of patients will develop lupus nephritis (LN); thus, early recognition and treatment is associated with better outcome. Interleukin 22 (IL-22) is involved in tissue inflammation and is regulated by interleukin 22 binding protein (IL-22BP). This study aimed to use IL-22BP as a non-invasive marker for disease activity in JSLE and LN. This is a cross-sectional study conducted on 82 subjects: 51 JSLE patients and 31 healthy controls of matched age and gender. Urinary IL-22BP was measured using enzyme-linked immunosorbent assay, and its level was correlated with different clinical and laboratory data in JSLE as well as Systemic Lupus Erythematous Disease Activity Index 2000 (SLEDAI-2k), renal SLEDAI-2k, and Systemic Lupus International Collaborating Clinics (SLICC) renal activity score which were used to assess overall disease and renal activity. Our results showed that urinary IL-22BP level was significantly higher in JSLE patients with mean level of 4.13 ± 1.10, as compared to controls 1.63 ± 0.61 (P value < 0.001); also, patients with active LN had urinary levels of IL-22BP (5.47 ± 1.03) higher than patients with active JSLE without LN (4.23 ± 0.72) and patients with non-active JSLE/LN (3.5 ± 0.65) with a highly significant P value < 0.001. There was a positive correlation with SLEDAI-2k, renal SLEDAI, and renal activity scores (P < 0.001). Urinary IL-22BP may be used as a non-invasive marker for assessment of disease activity in children with JSLE and LN.     

Gastric plexiform schwannoma in association with neurofibromatosis type 2

Plexiform schwannoma (PS) is an uncommon variant of schwannoma characterized by a multinodular (plexiform) growth pattern. It comprises up to 5 % of all schwannomas. The association between PS and neurofibromatosis type 1 or type 2 (NF1/NF2) is only rarely reported. Most cases of PS occur in the skin and subcutaneous soft tissue, with only a few reports of digestive tract involvement. We describe an 18-year-old male with NF2 who had bilateral vestibular schwannomas and multiple cutaneous PSs, and a 3-year history of abdominal pain. The patient ultimately underwent a distal gastrectomy for a partially obstructing submucosal antral mass, associated with an overlying ulcer. Histopathologic examination showed the mass to be a PS. The patient is alive and well, without symptoms, 12 months postoperatively. A review of the English language medical literature yielded only ten examples of PS arising in the digestive tract. Our patient is the first to be reported to have a gastric PS, and only the second patient to be reported with a digestive tract PS to have NF2, and the only patient reported to have both digestive tract and cutaneous PSs. Despite its rare occurrence with NF2, the finding of PS at any site should stimulate an examination for other manifestations of this disorder. Clinical Trial Registration: None.     

Development of an Arabic version of the National Eye Institute Visual Function Questionnaire as a tool to study eye diseases patients in Egypt

AIM:To develop and test an Arabic version of the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25).METHODS:NEI-VFQ-25 was translated into Arabic according to WHO translation guidelines. We enrolled adult consenting patients with bilateral chronic eye diseases who presented to 14 hospitals across Egypt from October to December 2012, and documented their clinical findings. Psychometric properties were then tested using STATA.RESULTS:We recruited 379 patients, whose mean age was (54.5±15)y. Of 46.2% were males, 227 had cataract, 31 had glaucoma, 23 had retinal detachment, 37 had diabetic retinopathy, and 61 had miscellaneous visual defects. Non-response rate and the floor and ceiling numbers of the Arabic version (ARB-VFQ-25) were calculated. Internal consistency was high in all subscales (except general health), with Cronbach-α ranging from 0.702-0.911. Test-retest reliability was high (intraclass correlation coefficient 0.79).CONCLUSION:ARB-VFQ-25 is a reliable and valid tool for assessing visual functions of Arabic speaking patients. However, some questions had high non-response rates and should be substituted by available alternatives. Our results support the importance of including self-reported visual functions as part of routine ophthalmologic examination.     

Three‐dimensional transesophageal echocardiography incremental value in a rare case of a bileaflet tricuspid valve

Detailed assessment of the tricuspid valve using two‐dimensional echocardiography is always challenging, as only two of three leaflets can be seen at a time. Three‐dimensional echocardiography can provide the enface view of the tricuspid valve that allows simultaneous visualization of all of the three leaflets. In a 42‐year‐old male patient scheduled for pulmonary endarterectomy, 3DTEE showed that the tricuspid valve is bileaflet, with one septal and another lateral leaflet. There were two commissures, one of them is anteriorly positioned and the other one is posterior. Our findings were confirmed intra‐operatively by direct surgical visualization of the tricuspid valve.