Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane

Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding.     

Catheter ablation guided by termination of postinfarction ventricular tachycardia by pacing with nonglobal capture.

OBJECTIVES: We prospectively investigated the prevalence and value of this criterion for identifying a target site for ablation in patients with postinfarction ventricular tachycardia (VT). BACKGROUND: Termination of postinfarction VT by pacing with nonglobal capture identifies a critical component of the reentrant circuit. METHODS: In a consecutive series of 34 patients with prior infarction (age 67 +/- 10 years, ejection fraction 0.26 +/- 0.1) referred for radiofrequency catheter ablation, mapping was performed in the left ventricle. At sites with abnormal electrograms, pacing was performed during VT. If VT terminated with nonglobal capture during the pacing train, radiofrequency energy was delivered. RESULTS: Sixty-two VTs (cycle length 450 +/- 84 ms) were mapped and targeted for radiofrequency ablation. Concealed entrainment was present at 101 endocardial sites. Among the 101 sites, VT terminated by pacing with nonglobal capture at 5 sites (5%). At 10 additional sites in 10 patients, VT terminated by pacing with nonglobal capture, and concealed entrainment could not be documented at these sites because of reproducible termination of the VT. An application of radiofrequency energy resulted in VT termination at all 15 sites where nonglobal capture was documented and the targeted VTs were no longer inducible after ablation. CONCLUSIONS: Termination of VT by pacing with nonglobal capture can be demonstrated in approximately one third of patients with postinfarction VT and is a specific criterion for identifying a critical component of the reentrant circuit, whether or not concealed entrainment can be documented at that site.     

Mechanism of atrial flutter occurring late after orthotopic heart transplantation with atrio-atrial anastomosis

OBJECTIVE: We sought to better define the electrophysiologic mechanism of atrial flutter in patients after heart transplantation. BACKGROUND: Atrial flutter is a recognized problem in the post-cardiac transplant population. The electrophysiologic basis of atrial flutter in this patient population is not completely understood. METHODS: Six patients with cardiac allografts and symptoms related to recurrent atrial flutter underwent diagnostic electrophysiologic study with electroanatomic mapping and radiofrequency catheter ablation. Comparison was made with a control non-transplant population of 11 patients with typical counterclockwise right atrial flutter. RESULTS: In each case, mapping showed typical counterclockwise activation of the donor-derived portion of the right atrium, with concealed entrainment shown upon pacing in the cavotricuspid isthmus (CTI). The anastomotic suture line of the atrio-atrial anastomosis formed the posterior barrier of the reentrant circuit. Ablation of the electrically active, donor-derived portion of the CTI was sufficient to terminate atrial flutter and render it noninducible. Comparison with the control population showed that the electrically active portion of the CTI was significantly shorter in patients with transplant-associated flutter and that ablation was accomplished with the same or fewer radiofrequency lesions. CONCLUSIONS: Atrial flutter in cardiac transplant recipients is a form of typical counterclockwise, isthmus-dependent flutter in which the atrio-atrial anastomotic suture line forms the posterior barrier of the reentrant circuit. Ablation in the donor-derived portion of the CTI is sufficient to create bidirectional conduction block and eliminate this arrhythmia. Ablation or surgical division of the donor CTI at the time of transplantation could prevent this arrhythmia.     

Tyrosinemia type 1 in pediatric nephrology: Not always straightforward

The main clinical features of tyrosinemia type 1 usually appear in the first months of life, including fever, diarrhea, vomiting, liver involvement, growth failure, and renal proximal tubulopathy with subsequent hypophosphatemic rickets. An early diagnosis is crucial in order to provide specific management and to prevent complications. Here, we report on two cases referred primarily to pediatric nephrologists for the diagnosis of “neonatal tubulopathy” and management of “X-linked hypophosphatemia (XLH),” respectively. Our aim is to emphasize that (1) even a mixed tubulopathy can reveal tyrosinemia, and (2) tyrosinemia is a classic differential diagnosis of XLH that should not be forgotten, especially in the era of the anti-FGF23 burosumab.     

Long-term single procedure efficacy of catheter ablation of atrial fibrillation

Background Two important limitations of the data regarding the outcomes of catheter ablation of atrial fibrillation (AF) are the short-term follow-up used in most published studies and the lack of single-procedure outcomes.Objective The objective was to report the long-term single-procedure outcomes at our center.Materials and methods The patient population was comprised of 200 consecutive patients who underwent ablation (133 men; age 56 ± 11 years). Atrial fibrillation was paroxysmal in 92 (46%). Success was defined as absence of symptomatic AF, off antiarrhythmic drug (AAD) after a single procedure.Results After a follow-up of 26 ± 11 months, the single-procedure long-term success rate was 28% with an additional 7% of patients demonstrating improvement. After including repeat procedures in 64 patients, the overall long-term success rate was 41% with 11% demonstrating improvement. Further subgroup analysis of 48 paroxysmal AF patients considered to be optimal candidates for the procedure, revealed a long-term success rate of 69% with an additional 4% demonstrating improvement. A major complication occurred in 7.9% of patients.Conclusion The results reveal that the long-term single-procedure success rate of catheter ablation of AF in a cohort of patients with predominantly non-paroxysmal AF is less than 40%. The inclusion of redo procedures resulted in an improvement in outcomes. A much higher success rate of 69% was achieved in patients with paroxysmal AF considered to be optimal candidates for this procedure. These results make it clear that further advances in the technique of catheter ablation of AF are needed to improve the safety and efficacy of this procedure. In order to be able to compare outcomes of various techniques in differing patient populations, we urge investigators to report long-term single procedure outcomes.This study was supported by The Norbert and Louise Grunwald Cardiac Arrhythmia Research Fund.     

Actinomyces graevenitzii pulmonary abscess mimicking tuberculosis in a healthy young man

Pulmonary actinomycosis is a rare disease that is often misdiag-nosed as tuberculosis or lung cancer. Actinomyces graevenitzii is a relatively new recognized Actinomyces species isolated from various clinical samples. The authors report a case of pulmonary actinomycosis caused by A graevenitzii. A computed tomography examination revealed an excavated consolidation in the middle right lobe of a previously healthy young man who presented with a long history of moderate cough. Cultures of the bronchoalveolar lavage fluid confirmed the diagnosis of pulmonary abscess caused by A gravenitzii. At the three-month follow-up consultation and, after six weeks of high-dose amoxicillin, the pulmonary lesion had completely disappeared.     

Protective Effect of Vitamin E Against Ethanol-Induced Hyperhomocysteinemia, DNA Damage, and Atrophy in the Developing Male Rat Brain

Background:  Chronic alcoholism leads to elevated plasma and brain homocysteine (Hcy) levels, as demonstrated by clinical investigations and animal experiments. It has been posited that elevated levels of Hcy mediate DNA damage, brain atrophy, and excitotoxicity. The current study sought to elucidate the effect of vitamin E on ethanol-induced hyperhomocysteinemia, DNA damage, and atrophy in the developing hippocampus and cerebellum of rats.
Methods:  Pregnant Wistar rats received ethanol with or without vitamin E from gestation day 7 throughout lactation. Weight changes in the brain, hippocampus and cerebellum, DNA damage, and Hcy levels in the plasma, hippocampus, and cerebellum of male offspring were measured at the end of lactation.
Results:  The results revealed that along with a significant decrease in brain, cerebellum, and hippocampus weights in animals that received alcohol, the levels of DNA damage and Hcy significantly increased. Significant amelioration of brain atrophy and DNA damage as well as restoration of the elevated level of Hcy to that of controls were found in vitamin E-treated rats.
Conclusions:  These findings strongly support the idea that ethanol intake by dams during pregnancy and lactation induces Hcy-mediated oxidative stress in the developing hippocampus and cerebellum of offspring rats, and that these effects can be alleviated by vitamin E as an antioxidant.     

Incidence and time course of early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation

Background: Although it is well recognized that recovery of pulmonary vein (PV) conduction is common among patients who fail atrial fibrillation (AF) ablation, little is known about the precise time course of recurrence.
Objective: To determine the incidence and time course of early recurrence of conduction after PV isolation during AF ablation.
Methods: The patient population was composed of 14 consecutive patients (9 men [64%]; age 56 ± 7 years) with AF who underwent radiofrequency catheter ablation via circumferential ablation with PV isolation, determined by a circular mapping catheter. After successful isolation of the PVs, repeat circular electrode recordings from each PV were obtained at 30 and 60 minutes.
Results: After complete isolation of all PVs, early PV recurrence was observed in 13 (93%) patients and 26 veins (50%). Seventeen veins (33%) showed a first recurrence at 30 minutes, while nine veins (17%) showed a first recurrence at 60 minutes.
Conclusion: The results reveal an extremely high rate of early recurrence of PV conduction following AF ablation. It is particularly notable that about one-fifth of the veins remained isolated at 30 minutes, but subsequently developed recurrence between 30 and 60 minutes. Of the veins that showed early recurrence, one-third developed a first recurrence at 60 minutes. These findings suggest that AF ablation procedures should incorporate a 60-minute waiting period after initial isolation in order to detect early recurrence of conduction.