Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents.

Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3'-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110α as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation, migration, survival) downstream of multiple RTKs. Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110α prevented onset and progression of pulmonary hypertension (PH) as well as right heart hypertrophy in vivo and even reversed established vascular remodeling and PH in various animal models. These effects were attributable to both inhibition of vascular proliferation and induction of apoptosis. Since this pathway is abundantly activated in human disease, p110α represents a central target in PH.

Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation.

The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2's protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/- ) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2-/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.

Periinterventional inflammation and blood transfusions predict postprocedural delirium after percutaneous repair of mitral and tricuspid valves.

OBJECTIVES: The aim of this study was to examine predictors and impact of postoperative delirium (POD) on outcome after percutaneous repair of mitral and tricuspid valves. BACKGROUND: POD is common in elderly patients and contributes to increased health care costs and worse outcome. Predictors of POD in percutaneous mitral or tricuspid valve procedures are unclear. METHODS: In a prospective single-center study, patients were screened for POD using the Confusion Assessment Method on the first and second postprocedural days, and up until 7 days in patients with clinical suspicion of delirium. Associations of POD with baseline characteristics, periprocedural outcome and mid-term mortality were examined. RESULTS: One hundred and seventy-seven patients were included (median age 78 years [72-82], 41.8% female) and median (IQR) follow-up was 489 (293-704) days. Patients developing POD (n = 16, 9%) did not differ in baseline and procedural characteristics but more often received postinterventional blood transfusions (37.5% vs. 9.9%, p value = 0.007) and suffered from infections (43.8% vs. 9.9%, p value = 0.001). Patients with POD showed worse survival (HR: 2.71 [1.27-5.78]; p = 0.01), with an estimated 1-year survival of 46 ± 13% compared to 80 ± 3% in patients without POD (log-rank p value 0.007). In multivariate Cox regression, POD remained a significant predictor of mid-term mortality (HR 4.75 [1.97-11.5]; p = 0.001). CONCLUSION: After percutaneous mitral or tricuspid valve repair, POD was independently associated with worse mid-term survival. Procedure- rather than patient-associated characteristics such as blood transfusions and infections emerged as important risk factors for development of POD. Considering the substantial prognostic impact of POD, further studies on its prevention are warranted to improve patient outcome.

Three-dimensional compared to two-dimensional transesophageal echocardiography for diagnosis of infective endocarditis.

PURPOSE: Transesophageal echocardiography is crucial for the diagnosis of infective endocarditis (IE). Use of three-dimensional transesophageal echocardiography (3D-TEE) could improve the reliability of echocardiographic findings. This study sought to determine the value of 3D-TEE in the diagnosis of IE in comparison to two-dimensional (2D)-TEE and 2D transthoracic echocardiography (2D-TTE). METHODS: In this prospective cohort study in a tertiary care university hospital 144 consecutive patients with clinically suspected IE were included. The patients were subjected to clinical, microbiological and echocardiographic evaluation (2D-TTE, 2D-TEE and 3D-TEE) and their clinical history evaluated retrospectively to establish a reference diagnosis of IE in accordance to current guideline recommendations. RESULTS: In 48 (33 %) patients the diagnosis of IE was established. 2D-TEE and 3D-TEE showed a sensitivity, specificity, positive and negative predictive value for diagnosis of IE of 94 % and 63, 90 and 95 %, 82 and 86 % and 97 and 83 %, respectively, with similar results in patients with native and prosthetic valves. Vegetations and abscess were detected in 43 and 5 patients with final diagnosis of IE by any of the assessed echocardiographic modalities, with only one case of vegetation detected by 3D-TEE only and not by 2D-TEE. CONCLUSIONS: In this cohort of patients with suspected IE, 3D-TEE showed substantial lower sensitivity and negative predictive value for diagnosis of IE when compared to 2D-TEE. 3D-TEE might provide additive diagnostic information with impact on clinical decisions only in individual cases.

The NAD(P)H oxidase inhibitor apocynin improves endothelial NO/superoxide balance and lowers effectively blood pressure in spontaneously hypertensive rats: comparison to calcium channel blockade.

The vascular NAD(P)H oxidase contributes to endothelial dysfunction and high blood pressure in the spontaneously hypertensive rat by enhancing superoxide production. We investigated the effects of apocynin, a NAD(P)H oxidase inhibitor, on blood pressure and vascular radical and nitric oxide formation in SHR and compared its effects to the calcium channel blocker nifedipine. Apocynin (over four weeks) lowered systolic blood pressure significantly and as effectively as nifedipine. Both apocynin and nifedipine significantly reduced superoxide production. In parallel, vascular nitric oxide production and ecNOS activity was significantly increased by apocynin treatment. Therefore, apocynin may be an effective antihypertensive drug in essential hypertension.