Human antigen R as a therapeutic target in pathological cardiac hypertrophy.

RNA binding proteins represent an emerging class of proteins with a role in cardiac dysfunction. We show that activation of the RNA binding protein human antigen R (HuR) is increased in the failing human heart. To determine the functional role of HuR in pathological cardiac hypertrophy, we created an inducible cardiomyocyte-specific HuR-deletion mouse and showed that HuR deletion reduces left ventricular hypertrophy, dilation, and fibrosis while preserving cardiac function in a transverse aortic constriction (TAC) model of pressure overload-induced hypertrophy. Assessment of HuR-dependent changes in global gene expression suggests that the mechanistic basis for this protection occurs through a reduction in fibrotic signaling, specifically through a reduction in TGF-ß (Tgfb) expression. Finally, pharmacological inhibition of HuR at a clinically relevant time point following the initial development of pathological hypertrophy after TAC also yielded a significant reduction in pathological progression, as marked by a reduction in hypertrophy, dilation, and fibrosis and preserved function. In summary, this study demonstrates a functional role for HuR in the progression of pressure overload-induced cardiac hypertrophy and establishes HuR inhibition as a viable therapeutic approach for pathological cardiac hypertrophy and heart failure.

Association of Preoperative Cell Counts With Outcomes After Operation for Congenital Heart Disease.

BACKGROUND: We examined the association of preoperative cell count abnormalities, which have been shown to be associated with outcomes in adult cardiac patients, with morbidity and mortality after operation for congenital heart disease (CHD) in children. METHODS: We performed a retrospective cohort study on 4,865 children undergoing cardiac operation from 2004 to 2014. Our exposures of interest were presence of preoperative lymphopenia (lymphocyte count ≤ 3,000 cells/µL), thrombocytopenia (platelet count < 150 × 103/µL), and neutrophilia (neutrophil count ≥ 7,000 cells/µL). Our outcomes of interest were mortality status, postoperative length of stay (LOS), and occurrence of postoperative complications. We performed logistic and linear regressions to determine the associations of preoperative cell counts with mortality, LOS, and complications, adjusting for age, sex, race or ethnicity, presence of a genetic syndrome, and Society of Thoracic Surgeons and European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality category. RESULTS: Overall mortality was 2.8%, median LOS was 6 days, and 7.6% of patients had postoperative complications. Lymphopenia was associated with increased odds of postoperative mortality (odds ratio 1.67, 95% confidence interval: 1.15 to 2.43, p = 0.007). Lymphopenia, thrombocytopenia, and neutrophilia were all associated with longer postoperative LOS. Lymphopenia and thrombocytopenia were associated with increased occurrence of postoperative sepsis, and neutrophilia was associated with need for postoperative mechanical circulatory support. CONCLUSIONS: In children undergoing CHD operation, preoperative lymphopenia is associated with increased in-hospital mortality postoperatively. Preoperative lymphopenia, neutrophilia, and thrombocytopenia are associated with longer postoperative LOS and with development of postoperative complications. Preoperative cell counts may serve as important prognostic markers in preoperative planning for patients with CHD.

PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice.

OBJECTIVE: PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS: PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient (Ldlr-/-) mice (8-12 weeks old) that were Par2+/+ or Par2-/- were fed a fat- and cholesterol-enriched diet for 12 or 24 weeks. PAR2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on nonhematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokines Ccl2 and Cxcl1 in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using isolated primary vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced Ccl2 and Cxcl1 mRNA expression and protein release into the supernatant resulting in less monocyte migration. CONCLUSIONS: Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting Ccl2- and Cxcl1-induced monocyte infiltration.

Accuracy of transesophageal echocardiography in the identification of postoperative intramural ventricular septal defects.

BACKGROUND: Intramural ventricular septal defects (VSDs), residual interventricular communications occurring after repair of conotruncal defects, are associated with poor postoperative outcomes. The ability of intraoperative transesophageal echocardiography (TEE) to identify intramural VSDs has not yet been evaluated. METHODS: Intraoperative TEE and postoperative transthoracic echocardiography (TTE) data in all patients undergoing all biventricular repair of conotruncal anomalies in our hospital between January 1, 2006, and June 30, 2013, were reviewed. The ability of TEE to accurately identify residual defects was assessed using postoperative TTE as the reference imaging modality. RESULTS: Intramural VSDs occurred in 34 of 337 patients evaluated; 19 were identified by both TTE and TEE, and 15 were identified by TTE only. Sensitivity was 56% and specificity was 100% for TEE to identify intramural VSDs. Peripatch VSDs were identified in 90 patients by both TTE and TEE, in 53 by TTE only, and in 15 by TEE only, yielding a sensitivity of 63% and specificity of 92%. Of the VSDs requiring catheterization or surgical reintervention, 6 of 7 intramural VSDs and all 5 peripatch VSDs were identified by intraoperative TEE. TEE guided the intraoperative decision to return to cardiopulmonary bypass (CPB) in an attempt to close residual defects in 12 patients with intramural VSDs and in 4 patients with peripatch VSDs seen after initial CPB; of these, 10 intramural VSDs and all 4 peripatch VSDs resolved or became smaller on final intraoperative TEE. CONCLUSIONS: TEE has modest sensitivity but high specificity for identifying intramural VSDs and can detect most defects requiring reintervention. Repeat attempts at closure in the index operation may successfully correct intramural VSDs identified by TEE.

Intramural Ventricular Septal Defect Is a Distinct Clinical Entity Associated With Postoperative Morbidity in Children After Repair of Conotruncal Anomalies.

BACKGROUND: Intramural ventricular septal defects (VSDs) are interventricular communications through right ventricular free wall trabeculations that can occur after repair of conotruncal anomalies. We assessed the prevalence of residual intramural VSDs and their effect on postoperative course. METHODS AND RESULTS: Children who underwent biventricular repair of a conotruncal anomaly from January 1, 2006, to June 30, 2013, and had a postoperative transthoracic echocardiogram were included. Images were reviewed for residual intramural or nonintramural VSDs. The primary outcome was a composite of mortality, extracorporeal membrane oxygenation use, and need for subsequent catheter or surgical VSD closure. The secondary outcome was postoperative hospital length of stay. A residual VSD was present in 256 of the 442 subjects (58%), of which 231 (90%) were <2 mm in size. Forty-nine patients (11%) had intramural VSDs, and 207 (47%) had nonintramural VSDs. Patients with intramural VSDs were more likely to reach the primary composite outcome compared with those with nonintramural VSDs or no residual VSD (14 of 49 [29%] versus 15 of 207 [7%] versus 6 of 186 [3%]; P<0.0001). In addition, those with intramural VSDs had longer postoperative hospital length of stay compared with those with nonintramural VSDs or no residual VSD (20 days [interquartile range, 11-42 days] versus 7 days [interquartile range, 5-14 days] versus 6 days [interquartile range, 4-11 days]; P=0.0001). These associations remained significant after adjustment for known risk factors for poor outcomes, including residual VSD size and operative complexity. CONCLUSIONS: Among residual VSDs after repair of conotruncal anomalies, intramural VSDs are uniquely associated with postoperative morbidity, mortality, and longer postoperative hospital length of stay. It is important to recognize intramural VSDs in the postoperative period.

Association between gastroesophageal reflux disease and laparoscopic sleeve gastrectomy.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common co-morbidity identified in obese patients. It is well established that patients with GERD and morbid obesity experience a marked improvement in their GERD symptoms after Roux-en-Y gastric bypass. Conflicting data exist for adjustable laparoscopic gastric banding and GERD. Laparoscopic sleeve gastrectomy (LSG) has become a popular adjunct to bariatric surgery in recent years. However, very little data exist concerning LSG and its effect on GERD. METHODS: A retrospective chart review was performed of 176 LSG patients from January 2006 to August of 2009. The preoperative and postoperative GERD symptoms were evaluated using follow-up surveys and chart review. RESULTS: Of the 176 patients, 85.7% of patients were women, with an average age of 45 years (range 22-65). The average preoperative body mass index was 46.6 kg/m(2) (range 33.2-79.6). The average excess body weight lost at approximately 6, 12, 24 months was calculated as 54.2%, 60.7%, and 60.3%, respectively. Of the LSG patients, 34.6% had preoperative GERD complaints. Postoperatively, 49% complained of immediate (within 30 d) GERD symptoms, 47.2% had persistent GERD symptoms that lasted >1 month after LSG, and 33.8% of patients were taking medication specifically for GERD after LSG. The most common symptoms were heartburn (46%), followed by heartburn associated with regurgitation (29.2%). CONCLUSION: In the present study, LSG correlated with the persistence of GERD symptoms in patients with GERD preoperatively. Also, patients who did not have GERD preoperatively had an increased risk of postoperative GERD symptoms.