Sporadic Form of Recurrent Atrial Myxoma: The Blob Strikes Back.

Cardiac myxoma is a benign neoplasm composed of stellate to plump, cytologically bland mesenchymal cells set in a myxoid stroma. Although benign, as they can lead to severe complications, they are often removed surgically. A 39-year-old female presented with a chief complaint of generalized fatigue. Patient had a history of a large 7cm x 2.5cm left atrial myxoma resected at the age of 32 years after she presented with symptoms of dyspnea on exertion. The dyspnea was due to prolapse of the mass through the mitral valve during diastole, leading to functional severe mitral stenosis. The mass was resected with clear margins confirmed on biopsy. On physical examination, heart rate was regular with no murmurs. No signs of congestive heart failure were noted. A 2D echo revealed a mobile structure in the left atrium along with mild mitral regurgitation. Cardiac MRI showed a 21mm x 9mm well defined, pedunculated, mobile mass in the left atrium arising from inter-atrial septum. The mass was hyperintense on T2 weighted images with patchy delayed hyper-enhancement consistent with recurrence of a myxoma. The patient underwent a repeat median sternotomy with the removal of left atrial mass and repair of atrial septum with hemashield patch. The mass was sent for pathological evaluation confirming the diagnosis of recurrent myxoma. On genetic testing, patient tested negative for mutations in PRKAR1A gene (mutated in up to 60%-80% cases with Carney complex), MEN1, RET and sarcoma (TP53) genes. Cardiac myxomas are rare primary benign tumors of the heart with a small recurrence rate. Follow-up studies have rarely reported recurrences after complete resection. However, in our case not only did the patient have the sporadic form of myxoma with recurrence, but it also occurred within three years of the previous resection despite complete removal with clear margins.

Palliative Care in Myocardial Infarction: Patient Characteristics and Trends of Service Utilization in a National Inpatient Sample.

INTRODUCTION: Myocardial infarction (MI) remains a leading cause of mortality. Palliative care (PC) has recently expanded in scope to include noncancer-related conditions. There is little data available regarding the use of PC in critical MI patients. METHODS: We used discharge data from the National Inpatient Sample for the years 2012 to 2014. We examined discharges with a primary diagnosis of MI. We measured the rate of PC referral, trend in utilization during the study period and possible predictors of PC utilization. RESULTS: Among 1 667 520 discharges of those patients ≥18 years of age and with a primary diagnosis of MI, use of PC was seen in 2.5% of all patients and in 24% of patients who died. In a multivariable logistic regression, we found the presence of cancer, cardiogenic shock, dementia, stroke, hemiplegia, the use of circulatory support, and mechanical ventilation were associated with higher likelihood of PC referral. Palliative care referral increased during the study period, odds ratio of 1.18 per year (95% confidence interval: 1.14-1.21; P value <.001). Palliative care was not associated with prolonged length of stay. CONCLUSION: Several comorbidities were associated with the use of PC, most notably the use of mechanical ventilation and the presence of metastatic cancer. There was a trend of increasing use of PC during the study period.

G-protein-coupled receptor kinase interacting protein-1 is required for pulmonary vascular development.

BACKGROUND: The G-protein-coupled receptor kinase interacting protein-1 (GIT1) is a multidomain scaffold protein that participates in many cellular functions including receptor internalization, focal adhesion remodeling, and signaling by both G-protein-coupled receptors and tyrosine kinase receptors. However, there have been no in vivo studies of GIT1 function to date. METHODS AND RESULTS: To determine essential functions of GIT1 in vivo, we generated a traditional GIT1 knockout mouse. GIT1 knockout mice exhibited approximately 60% perinatal mortality. Pathological examination showed that the major abnormality in GIT1 knockout mice was impaired lung development characterized by markedly reduced numbers of pulmonary blood vessels and increased alveolar spaces. Given that vascular endothelial growth factor (VEGF) is essential for pulmonary vascular development, we investigated the role of GIT1 in VEGF signaling in the lung and cultured endothelial cells. Because activation of phospholipase-Cgamma (PLCgamma) and extracellular signal-regulated kinases 1/2 (ERK1/2) by angiotensin II requires GIT1, we hypothesized that GIT1 mediates VEGF-dependent pulmonary angiogenesis by modulating PLCgamma and ERK1/2 activity in endothelial cells. In cultured endothelial cells, knockdown of GIT1 decreased VEGF-mediated phosphorylation of PLCgamma and ERK1/2. PLCgamma and ERK1/2 activity in lungs from GIT1 knockout mice was reduced postnatally. CONCLUSIONS: Our data support a critical role for GIT1 in pulmonary vascular development by regulating VEGF-induced PLCgamma and ERK1/2 activation.

GIT1 mediates thrombin signaling in endothelial cells: role in turnover of RhoA-type focal adhesions.

Thrombin mediates changes in endothelial barrier function and increases endothelial permeability. A feature of thrombin-enhanced endothelial hyperpermeability is contraction of endothelial cells (ECs), accompanied by formation of focal adhesions (FAs). Recently, a G protein-coupled receptor kinase-interacting protein, GIT1, was shown to regulate FA disassembly. We hypothesized that GIT1 modulates thrombin-induced changes in FAs. In human umbilical vein ECs (HUVECs), thrombin recruited GIT1 to FAs, where GIT1 colocalized with FAK and vinculin. Recruitment of GIT1 to FAs was dependent on activation of the small GTPase RhoA, and Rho kinase, as demonstrated by adenoviral transfection of dominant-negative RhoA and treatment with Y-27632. Thrombin stimulated GIT1 tyrosine phosphorylation with a time course similar to FAK phosphorylation in a Rho kinase- and Src-dependent manner. Depletion of GIT1 with antisense GIT1 oligonucleotides had no effect on basal cell morphology, but increased cell rounding and contraction of HUVECs, increased FA formation, and increased FAK tyrosine phosphorylation in response to thrombin, concomitant with increased endothelial hyperpermeability. These data identify GIT1 as a novel mediator in agonist-dependent signaling in ECs, demonstrate that GIT1 is involved in cell shape changes, and suggest a role for GIT1 as a negative feedback regulator that augments recovery of cell contraction.

Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism.

c-Jun NH2-terminal kinase (JNK) is activated by a number of cellular stimuli including reactive oxygen species (ROS). Previous studies have demonstrated that fluid shear stress (flow) inhibits cytokine-induced JNK activation in endothelial cells (ECs). In the present study, we show JNK activation by ROS in ECs and hypothesized that flow inhibits ROS-induced JNK activation in ECs via modulation of cellular protection systems against ROS. JNK was activated by 300 micro mol/L hydrogen peroxide (H2O2) in bovine lung microvascular ECs (BLMVECs) with a peak at 60 minutes after stimulation (6.3+/-1.2-fold increase). Preexposure of BLMVECs to physiological steady laminar flow (shear stress=12 dyne/cm2) for 10 minutes significantly decreased H2O2-induced JNK activation. Thioredoxin and glutathione are cellular antioxidants that protect cells against ROS. Flow induced a significant increase in the ratio of reduced glutathione to oxidized glutathione consistent with a 1.6-fold increase in glutathione reductase (GR) activity. Preincubation of BLMVECs with the GR inhibitor, 1,3 bis-(2 chloroethyl)-1-nitrosourea, abolished the inhibitory effect of flow. In contrast, preincubation of BLMVECs with azelaic acid, a specific inhibitor for thioredoxin reductase, did not alter the effect of flow on H2O2-induced JNK activation. Overexpression of GR mimicked the effect of flow to inhibit JNK activation. These results suggest that flow activates GR, an important regulator of the intracellular redox state of glutathione, and exerts a protective mechanism against oxidative stress in endothelial cells.

Atheroprotective Mechanisms Activated by Fluid Shear Stress in Endothelial Cells.

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, while laminar flow and high shear stress are atheroprotective. Well characterized atheroprotective mechanisms include inhibition of thrombosis (increased tissue-type plasminogen activator and decreased plasminogen activator inhibitor-1), inhibition of endothelial cell apoptosis, limitation of permeability (uptake of low-density lipoprotein), prevention of white blood cell binding and transmigration (no expression of adhesion molecules such as intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1] and no release of monocyte chemotactic protein-1) and increased bioavailability of nitric oxide (because of increased expression of endothelial nitric oxide synthase and manganese superoxide dismutase). Our lab has investigated flow-mediated inhibition of inflammatory cytokine action. In particular, we have shown that flow prevents tumor necrosis factor-alpha (TNF-alpha) mediated signal transduction. TNF regulates inflammatory gene expression (e.g., ICAM-1 and VCAM-1) in endothelial cells, in part, by stimulating mitogen activated protein (MAP) kinases that phosphorylate transcription factors. We hypothesized that fluid shear stress inhibits TNF inflammatory effects on endothelial cells by inhibiting TNF mediated activation of the c-Jun N-terminal kinase. To test this hypothesis, we determined the effects of steady laminar flow on TNF-stimulated activity of c-Jun N-terminal kinase. The results show that flow inhibits c-Jun N-terminal kinase activation through multiple mechanisms, including stimulation of counter-regulatory MAP kinases (extracellular signal regulated kinases [ERK]1/2 and ERK5) and inhibition of apoptosis signal-regulated kinase. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms. These multiple mechanisms offer attractive targets for new drug therapies aimed at limiting atherosclerosis development and progression. (c) 2002 Prous Science. All rights reserved.