Relationship between B-type natriuretic peptide and invasive haemodynamics in patients with severe aortic valve stenosis.

AIMS: In patients with aortic stenosis (AS), B-type natriuretic peptide (BNP) is a prognostic marker. However, there is little information on the association between BNP and invasive haemodynamics in AS. The aim of the present study was to assess the hitherto not well-defined relationship between BNP and invasive haemodynamics in patients with severe AS undergoing aortic valve replacement (AVR) with a view to understand the link between high BNP and poor prognosis in these patients. In particular, we were interested in the association between BNP and combined pre-capillary and post-capillary pulmonary hypertension (CpcPH). METHODS AND RESULTS: BNP was measured in 252 patients (age 74 ± 10 years, 58% male patients) with severe AS [indexed aortic valve area 0.4 ± 0.1 cm2 /m2 and left ventricular ejection fraction (LVEF) 57 ± 12%] the day before cardiac catheterization. Patients were followed for a median (interquartile range) period of 3.1 (2.3-4.3) years after surgical (n = 157) or transcatheter (n = 95) AVR. The prevalence of CpcPH (mean pulmonary artery pressure ≥ 25 mmHg, mean pulmonary artery wedge pressure > 15 mmHg, and pulmonary vascular resistance > 3 Wood units) was 13%. The median BNP plasma concentration was 188 (78-452) ng/L. The indexed aortic valve area was similar across BNP quartiles (P = 0.21). Independent predictors of higher BNP (ln transformed) included lower haemoglobin (beta = -0.18; P < 0.001), lower LVEF (beta = -0.20; P < 0.001), more severe mitral regurgitation (beta = 0.20; P < 0.001), higher mean pulmonary artery wedge pressure (beta = -0.37; P < 0.001), and higher pulmonary vascular resistance (beta = 0.21; P < 0.001). In a multivariate model with CpcPH rather than its haemodynamic components, CpcPH was independently associated with higher BNP (0.21; P < 0.001). Higher ln BNP was associated with higher mortality [hazard ratio 1.90 (95% confidence interval 1.33-2.71); P < 0.001] in the univariate analysis. Patients in the third and fourth BNP quartiles had a more than six-fold risk of death compared with patients in the first and second quartiles [hazard ratio 6.29 (95% confidence interval 1.86-21.27); P = 0.003]. In the multivariate analysis, lower LVEF [hazard ratio 0.96 (95% confidence interval 0.94-0.99) per 1% increase; P = 0.01] and CpcPH [hazard ratio 4.58 (95% confidence interval 1.89-11.09); P = 0.001] but not BNP were independently associated with mortality. The areas under the receiver operator characteristics curve for BNP for the prediction of CpcPH and mortality were 0.88 and 0.74, respectively. CONCLUSIONS: In patients with severe AS, higher BNP is a marker of the presence of CpcPH and its contributors. The association between BNP and such an adverse haemodynamic profile at least in part explains the ability of BNP to predict long-term post-AVR mortality.

Pulmonary Hypertension in Aortic and Mitral Valve Disease.

In patients with aortic and/or mitral valve disease the presence of pulmonary hypertension (PH) indicates a decompensated state of the disease with left ventricular and left atrial dysfunction and exhausted compensatory mechanism, i.e., a state of heart failure. Pulmonary hypertension in this context is the consequence of the backwards transmission of elevated left atrial pressure. In this form of PH, pulmonary vascular resistance is initially normal (isolated post-capillary PH). Depending on the extent and chronicity of left atrial pressure elevation additional pulmonary vascular remodeling may occur (combined pre- and post-capillary PH). Mechanical interventions for the correction of valve disease often but not always reduce pulmonary pressures. However, the reduction in pulmonary pressures is often modest, and persistent PH in these patients is common and a marker of poor prognosis. In the present review we discuss the pathophysiology and clinical impact of PH in patients with aortic and mitral valve disease, the comprehensive non-invasive and invasive diagnostic approach required to define treatment of PH, and recent insights from mechanistic studies, registries and randomized studies, and we provide an outlook regarding gaps in evidence, future clinical challenges, and research opportunities in this setting.

Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP.

In order to address the debatable prognostic role of MYC rearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYC rearrangements by fluorescence in situ hybridization in 563 cases using break-apart probes and IGH/MYC dual-fusion probes. Concurrent BCL2 and BCL6 aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYC rearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYC rearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYC rearrangements were more likely to be treatment resistant (P<0.0001). All types of MYC rearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYC rearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2 aberrations but not of BCL6 aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYC rearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYC rearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYC rearrangements. We conclude that MYC rearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup.

MALDI imaging combined with hierarchical clustering as a new tool for the interpretation of complex human cancers.

Proteomics analyses have been exploited for the discovery of novel biomarkers for the early recognition and prognostic stratification of cancer patients. These analyses have now been extended to whole tissue sections by using a new tool, that is, MALDI imaging. This allows the spatial resolution of protein and peptides and their allocation to histoanatomical structures. Each MALDI imaging data set contains a large number of proteins and peptides, and their analysis can be quite tedious. We report here a new approach for the analysis of MALDI imaging results. Mass spectra are classified by hierarchical clustering by similarity and the resulting tissue classes are compared with the histology. The same approach is used to compare data sets of different patients. Tissue sections of gastric cancer and non-neoplastic mucosa obtained from 10 patients were forwarded to MALDI-Imaging. The in situ proteome expression was analyzed by hierarchical clustering and by principal component analysis (PCA). The reconstruction of images based on principal component scores allowed an unsupervised feature extraction of the data set. Generally, these images were in good agreement with the histology of the samples. The hierarchical clustering allowed a quick and intuitive access to the multidimensional information in the data set. It allowed a quick selection of spectra classes representative for different tissue features. The use of PCA for the comparison of MALDI spectra from different patients showed that the tumor and non-neoplastic mucosa are separated in the first three principal components. MALDI imaging in combination with hierarchical clustering allows the comprehensive analysis of the in situ cancer proteome in complex human cancers. On the basis of this cluster analysis, classification of complex human tissues is possible and opens the way for specific and cancer-related in situ biomarker analysis and identification.