Mitchell J. Coplan

Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding.

Background: Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding. Methods: Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2–blocking antibody. Ang-2 gene expression was measured by reverse transcription–polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar. Results: Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (P=0.001 and P<0.001, respectively). This corresponded to an increased angiogenic potential of serum from patients with LVADs (P<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (P=0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (P<0.001), which was reduced with thrombin receptor blockade (P=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean (P=0.003). Conclusions: Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.

Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices

BACKGROUND Non-surgical bleeding (NSB) due to angiodysplasia is common in left ventricular assist device (LVAD) patients. Thrombin-induced angiopoietin-2 (Ang-2) expression in LVAD patients leads to altered angiogenesis and is associated with lower angiopoietin-1 (Ang-1) and increased NSB. However, the mechanism for decreased Ang-1, made by pericytes, is unknown and the origin of thrombin in LVAD patients is unclear. We hypothesized that high tumor necrosis factor-α (TNF-α) levels in LVAD patients induce pericyte apoptosis, tissue factor (TF) expression and vascular instability. METHODS We incubated cultured pericytes with serum from patients with heart failure (HF), LVAD or orthotopic heart transplantation (OHT), with or without TNF-α blockade. We performed several measurements: Ang-1 expression was assessed by reverse transcript-polymerase chain reaction (RT-PCR) and pericyte death fluorescently; TF expression was assessed by RT-PCR in cultured endothelial cells incubated with patient plasma with or without TNF-α blockade; and TF expression was assessed in endothelial biopsy samples from these patients by immunofluorescence. We incubated cultured endothelial cells on Matrigel with patient serum with or without TNF-α blockade and determined tube formation by microscopy. RESULTS Serum from LVAD patients had higher levels of TNF-α, suppressed Ang-1 expression in pericytes, and induced pericyte death, and there was accelerated endothelial tube formation compared with serum from patients without LVADs. TF was higher in both plasma and endothelial cells from LVAD patients, and plasma from LVAD patients induced more endothelial TF expression. All of these effects were reversed or reduced with TNF-α blockade. High levels of TNF-α were associated with increased risk of NSB. CONCLUSIONS Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis and expression of TF and Ang-1.

Cardiology Consultation in the Emergency Department Reduces Re-hospitalizations for Low-Socioeconomic Patients with Acute Decompensated Heart Failure

BACKGROUND Re-hospitalization after discharge for acute decompensated heart failure is a common problem. Low-socioeconomic urban patients suffer high rates of re-hospitalization and often over-utilize the emergency department (ED) for their care. We hypothesized that early consultation with a cardiologist in the ED can reduce re-hospitalization and health care costs for low-socioeconomic urban patients with acute decompensated heart failure. METHODS There were 392 patients treated at our center for acute decompensated heart failure who received standardized education and follow-up. Patients who returned to the ED received early consultation with a cardiologist; 392 patients who received usual care served as controls. Thirty- and 90-day re-hospitalization, ED re-visits, heart failure symptoms, mortality, and health care costs were recorded. RESULTS Despite guideline-based education and follow-up, the rate of ED re-visits was not different between the groups. However, the rate of re-hospitalization was significantly lower in patients receiving the intervention compared with controls (odds ratio 0.592), driven by a reduction in the risk of readmission from the ED (0.56 vs 0.79, respectively). Patients receiving the intervention accumulated 14% fewer re-hospitalized days than controls and 57% lower 30-day total health care cost. Despite the reduction in health care resource consumption, mortality was unchanged. After accounting for the total cost of intervention delivery, the health care cost savings was substantially greater than the cost of intervention delivery. CONCLUSION Early consultation with a cardiologist in the ED as an adjunct to guideline-based follow-up is associated with reduced re-hospitalization and health care cost for low-socioeconomic urban patients with acute decompensated heart failure.

ANGIOPOIETIN-2 MEDIATES ABNORMAL ANGIOGENESIS AND NON-SURGICAL BLEEDING IN PATIENTS WITH CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICES

Non-surgical bleeding (NSB) is the most common adverse event in patients with Continuous-Flow Left Ventricular Assist Devices (LVADs) and is attributed to the development of arteriovenous malformations (AVMs) a process which may reflect altered angiogenesis. Angiopoietin-2 (Ang-2) is a potent