Medical Management of Recurrent Left Ventricular Assist Device Thrombosis in a Patient With Biventricular Assist Devices.

Ventricular assist device (VAD) pump thrombosis is a known complication and while the preferred standard treatment is surgical pump exchange this procedure is not without risk and for some patients the risks are prohibitive. This is a case of a 68-year-old female with bilateral HeartWare ventricular assist devices (HVAD) implanted as destination therapy who presented with signs of recurrent pump thrombosis. Surgical pump exchange was deemed to confer prohibitive risk due to her underlying medical co-morbidities and therefore not an option for treatment. After careful consideration of possible options for treatment, she received systemic thrombolysis (Alteplase 5 mg IV bolus followed by 3 mg/hour infusion for 10 hours through a central line) which was successful. This case highlights, not only the rarity of bilateral VADs as destination therapy, but also demonstrates the safety and efficacy of using systemic thrombolytics in patients with bilateral HVADs for treatment of pump thrombosis.

Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells.

Expression of vascular endothelial growth factor (VEGF) is tightly regulated to achieve normal angiogenesis. The objective was to examine regulation of VEGF by the activin-like kinase receptors (ALKs) ALK1 and ALK5. Transforming growth factor beta1 (TGFbeta1) and bone morphogenetic protein-9 (BMP-9) enhanced and suppressed VEGF expression, respectively, in aortic endothelial cells, as determined by real-time polymerase chain reaction, immunoblotting, cell proliferation, and tube formation. The use of small interfering RNA revealed that TGFbeta1 stimulated VEGF expression by activating ALK5, TGFbeta type II receptor, and SMAD2, whereas BMP-9 suppressed it by activating ALK1, BMP type II receptor, and SMAD1. ALK1 signaling occurred independently of ALK5 activity. Partial ALK1 deficiency in vitro and in vivo resulted in elevated VEGF expression. In vitro, increased BMP-9 levels normalized VEGF expression in cells with partial, but not severe, ALK1 deficiency. Time course experiments revealed that an increase in ALK1 expression induced by BMP-4, an angiogenic stimulus, preceded induction of ALK5 and VEGF in control cells. In ALK1-deficient cells, however, VEGF expression occurred earlier and was abnormally high, even though ALK5 was not induced. Our results suggest that ALK1 and ALK5 are both essential for correct regulation of VEGF, and that disruption of either pathway leads to disease.

High-density lipoproteins affect endothelial BMP-signaling by modulating expression of the activin-like kinase receptor 1 and 2.

OBJECTIVE: High-density lipoproteins (HDL) have antiinflammatory effects on the vascular endothelium. Because bone morphogenetic proteins (BMPs) are known to be inflammatory mediators, we examined the effect of HDL on BMP signaling. METHODS AND RESULTS: Increasing concentrations of HDL progressively enhanced expression of the activin-like kinase receptor (ALK)1 and ALK2 in human aortic endothelial cells as determined by real-time polymerase chain reaction and immunoblotting. Induction of ALK1 was a result of enhanced ALK2 expression as determined by siRNA interference, and was associated with increased levels of vascular endothelial growth factor (VEGF) and matrix Gla protein (MGP). The HDL-induction of ALK2 was dependent on BMP-signaling, and affected coregulation of the ALK2 gene by the homeodomain proteins MSX2, DLX3, and DLX5, as determined by reporter gene assays, siRNA interference, and chromatin immunoprecipitation. Apolipoprotein A-I transgenic mice, known to have high HDL and inhibition of atherogenesis, exhibited similar changes in aortic gene expression as seen in endothelial cells treated with HDL in vitro. CONCLUSIONS: We conclude that HDL benefits the arterial wall by allowing for enhanced ALK1 and ALK2 signaling, resulting in an increase of VEGF and MGP, essential for endothelial cell survival and prevention of vascular calcification, respectively.