Aims Heart failure (HF) patients show cognitive and mood impairments, including short-term memory loss and depression, adversely impacting quality of life and self-care management. Brain regions, including the hippocampus, a structure significantly involved in memory and mood, show injury in HF, but the integrity of specific hippocampal subregions is unclear. Methods and results To assess regional hippocampal volume loss, we evaluated 17 HF patients (mean age ± SD, 54.4 ± 2.0 years; 12 male, LVEF 28.3 ± 6.8%; NYHA Class II/III 94%/6%) and 34 healthy control subjects (52.3 ± 1.3 years; 24 male) using high-resolution T1-weighted magnetic resonance imaging and evaluated localized surface changes with morphometric procedures. Hippocampi were manually outlined, and volumes calculated from normalized tracings. Volume differences between groups were assessed by two-sample t-tests, and regional differences were assessed by surface morphometry. HF patients exhibited smaller hippocampal volumes than controls (Right: 3060±146 vs. 3478±94 mm3; p = 0.02, Left: 3021±145 vs. 3352±98 mm3; p = 0.06). Volume reductions were detected principally in CA1, an area integral to an array of learning and memory functions, as well as in mid- to posterior CA3 and subiculum. Conclusion The hippocampus shows regional volume reduction in HF, which may contribute to short-term memory loss and depression associated with the condition.
The Epidermal Growth Factor Receptor is frequently expressed in triple-negative breast cancer and is a marker of poor prognosis in this patient population. Because activating mutations in this kinase are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the six known EGFR ligands, TGFalpha was expressed more highly in triple-negative breast tumors than in tumors of other subtypes. TGFalpha is synthesized as a transmembrane precursor requiring TACE/ADAM17-dependent proteolytic release in order to activate its receptor. In this study we show that an inhibitor of this proteolytic release blocks invasion, migration and colony formation by several triple-negative breast cancer cell lines. Each of the effects of the drug was reversed upon expression of a soluble TGFalpha mutant which does not require TACE activity, implicating this growth factor as a key metalloproteinase substrate for these phenotypes. Together, these data demonstrate that TACE-dependent TGFalpha shedding is a key process driving EGFR activation and subsequent proliferation and invasion in triple-negative breast cancer cell lines.
Background Intraoperative or post procedure right ventricular (RV) dysfunction confers a poor prognosis in the post-operative period. Conventional predictors for RV function are limited due the effect of cardiac surgery on traditional RV indices; novel echocardiographic techniques hold the promise to improve RV functional stratification. Methods Comprehensive echocardiographic data were collected prospectively during elective cardiac surgery. Tricuspid annular plane systolic excursion (TAPSE), peak RV systolic velocity (S′), and RV fractional area change (FAC) were quantified on transesophageal echo (TEE). RV global and regional (septal and free wall) longitudinal strain was quantified using speckle-tracking echo in RV-focused views. Two intraoperative time points were used for comparison: pre-sternotomy (baseline) and after chest closure. Results The population was comprised of 53 patients undergoing cardiac surgery [15.1% coronary artery bypass graft (CABG) only, 28.3% valve only, 50.9% combination (e.g. valve/CABG, valve/aortic graft) surgeries], among whom 38% had impaired RV function at baseline defined as RV FAC < 35%. All conventional RV functional indices including TAPSE, S′ and FAC declined immediately following CPB (1.5 ± 0.3 vs.1.1 ± 0.3 cm, 8.0 ± 2.1 vs. 6.2 ± 2.5 cm/s, 36.8 ± 9.3 vs. 29.3 ± 10.6%; p < 0.001 for all). However, left ventricular (LV) and RV hemodynamic parameters remained unchanged (LV ejection fraction (EF): 56.8 ± 13.0 vs. 55.8 ± 12.9%; p = 0.40, pulmonary artery systolic pressure (PASP): 26.5 ± 7.4 vs 27.3 ± 6.7 mmHg; p = 0.13). Speckle tracking echocardiographic data demonstrated a significant decline in RV global longitudinal strain (GLS) [19.0 ± 6.5 vs. 13.5 ± 6.9%, p < 0.001]. Pre-procedure FAC, GLS and free wall strain predicted RV dysfunction at chest closure (34.7 ± 9.1 vs. 41.6 ± 8.1%, p = 0.01, 17.7 ± 6.5 vs. 21.8 ± 5.4%; p = 0.03, 20.3 ± 6.4 vs. 24.2 ± 5.8%; p = 0.04), whereas traditional linear RV indices such as TAPSE and RV S′ at baseline had no impact on intraoperative RV dysfunction ( p = NS for both). Conclusions Global and regional RV function, as measured by 2D indices and strain, acutely decline intraoperatively. Impaired RV strain is associated with intraoperative RV functional decline and provides incremental value to traditional RV indices in predicting those who will develop RV dysfunction.
Opinion Statement Right ventricular (RV) structure and function is clinically important in a wide range of conditions. While conventional echocardiography (echo) methods are widely used, its limitations in RV assessment due its complex geometry are well recognized. New applications of traditional echo methods as well as emerging echo techniques including 3-dimensional (3D) echo and speckle tracking strain have the potential to overcome limitations of conventional echo though widespread clinical use remains to be seen. Volumetric methods using cardiac magnetic resonance (CMR) and computed tomography (CT) provide accurate assessment of RV function without geometric assumptions. In addition, tissue characterization imaging for myocardial scar and fat using CMR and CT provides important information regarding the RV beyond structure and function alone and has clinical applications for diagnosis and prognosis in a broad range of pathologies. Limitations also exist for these two advanced modalities including availability and patient suitability for CMR and need for contrast and radiation exposure for CT. The complementary role of each modality for the RV as well as emerging evidence for the use of each imaging method in diagnosis and management of RV pathologies are outlined in this study.
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