Impact of Regional Left Ventricular Function on Outcome for Patients with AL Amyloidosis

Objectives

The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy.

Background

Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome.

Methods

LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days.

Results

Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35% vs. compensated 78%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14%, mild 27%, intermediate 67%, and severe 64%). Mid-septum LSsys<11% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival.

Conclusions

Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy.     

Permanent Cardiac Sarcomere Changes in a Rabbit Model of Intrauterine Growth Restriction

Background

Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.

Methods and Results

IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.

Conclusion

The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.     

Validation of numerical flow simulations against in vitro phantom measurements in different type B aortic dissection scenarios

An aortic dissection (AD) is a serious condition defined by the splitting of the arterial wall, thus generating a secondary lumen [the false lumen (FL)]. Its management, treatment and follow-up are clinical challenges due to the progressive aortic dilatation and potentially severe complications during follow-up. It is well known that the direction and rate of dilatation of the artery wall depend on haemodynamic parameters such as the local velocity profiles, intra-luminal pressures and resultant wall stresses. These factors act on the FL and true lumen, triggering remodelling and clinical worsening. In this study, we aimed to validate a computational fluid dynamic (CFD) tool for the haemodynamic characterisation of chronic (type B) ADs. We validated the numerical results, for several dissection geometries, with experimental data obtained from a previous in vitro study performed on idealised dissected physical models. We found a good correlation between CFD simulations and experimental measurements as long as the tear size was large enough so that the effect of the wall compliance was negligible.     

Impact of traffic related air pollution indicators on non-cystic fibrosis bronchiectasis mortality: a cohort analysis

Background

Mortality in non-cystic fibrosis bronchiectasis (NCFB) is known to be influenced by a number of factors such as gender, age, smoking history and Pseudomonas aeruginosa, but the impact of traffic related air pollution indicators on NCFB mortality is unknown.

Methods

We followed 183 patients aged 18 to 65 years with a HRCT proven diagnosis of NCFB and typical symptoms, who had visited the outpatient clinic at the University Hospital of Leuven, Belgium, between June 2006 and October 2012. We estimated hazard ratios (HR) for mortality in relation to proximity of the home to major roads and traffic load, adjusting for relevant covariables (age, gender, disease severity, chronic macrolide use, smoking history, socioeconomic status and Pseudomonas aeruginosa colonization status).

Results

Fifteen out of the 183 included patients died during the observation period. Residential proximity to a major road was associated with the risk of dying with a HR 0.28 (CI 95% 0.10-0.77; p = 0.013) for a tenfold increase in distance to a major road. Mortality was also associated with distance-weighted traffic density within 100 meters (HR for each tenfold increase in traffic density 3.80; CI 95% 1.07-13.51; p = 0.04) and 200 meters from the patient’s home address (HR for each tenfold increase in traffic density 4.14; CI 95% 1.13-15.22; p = 0.032).

Conclusion

Traffic-related air pollution appears to increase the risk of dying in patients with NCFB.

Trial registration

The study was approved by the local ethical committee of the UZ Leuven, Belgium (ML-5028), registered at ClinicalTrial.gov ({"type":"clinical-trial","attrs":{"text":"NCT01906047","term_id":"NCT01906047"}}NCT01906047).     

Predictive Value of Assessing Diastolic Strain Rate on Survival in Cardiac Amyloidosis Patients with Preserved Ejection Fraction

Objectives

Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSR_dias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%).

Background

Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LS_sys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSR_dias also related to outcome in these patients.

Methods

Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LS_sys and LSR_dias were obtained in six LV segments from apical 4-chamber views.

Results

Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5–35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6±2 vs. 8±3 mm), global LSR_dias and basal-septal LSR_dias were significantly lower in non-survivors than in survivors (all p<0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LS_sys, global LSR_dias, basal-septal LSR_dias and E/LSR_dias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR]  = 1.96, 95% confidence interval [CI] 1.17–3.26, P = 0.010), global LSR_dias (HR = 7.30, 95% CI 2.08–25.65, P = 0.002), and E/LSR_dias (HR = 2.98, 95% CI 1.54–5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSR_dias was optimal at a cutoff value of 0.85 S⁻¹ (sensitivity 68%, specificity 67%). Global LSR_dias <0.85 S⁻¹ predicted a 4-fold increased mortality in CA patients with preserved LVEF.

Conclusions

STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF.     

An investigation on performance of Significance Analysis of Microarray (SAM) for the comparisons of several treatments with one control in the presence of small-variance genes

One of multiple testing problems in drug finding experiments is the comparison of several treatments with one control. In this paper we discuss a particular situation of such an experiment, i.e., a microarray setting, where the many-to-one comparisons need to be addressed for thousands of genes simultaneously. For a gene-specific analysis, Dunnett's single step procedure is considered within gene tests, while the FDR controlling procedures such as Significance Analysis of Microarrays (SAM) and Benjamini and Hochberg (BH) False Discovery Rate (FDR) adjustment are applied to control the error rate across genes. The method is applied to a microarray experiment with four treatment groups (three microarrays in each group) and 16,998 genes. Simulation studies are conducted to investigate the performance of the SAM method and the BH-FDR procedure with regard to controlling the FDR, and to investigate the effect of small-variance genes on the FDR in the SAM procedure.     

The distal hinge of the reactive site loop and its proximity: a target to modulate plasminogen activator inhibitor-1 activity

The serpin plasminogen activator inhibitor type 1 (PAI-1) plays a regulatory role in various physiological processes (e.g. fibrinolysis and pericellular proteolysis) and forms a potential target for therapeutic interventions. In this study we identified the epitopes of three PAI-1 inhibitory monoclonal antibodies (MA-44E4, MA-42A2F6, and MA-56A7C10). Differential cross-reactivities of these monoclonals with PAI-1 from different species and sequence alignments between these PAI-1s, combined with the three-dimensional structure, revealed several charged residues as possible candidates to contribute to the respective epitopes. The production, characterization, and subsequent evaluation of a variety of alanine mutants using surface plasmon resonance revealed that the residues His(185), Arg(186), and Arg(187) formed the major sites of interaction for MA-44E4. In contrast, the epitopes of MA-42A2F6 and MA-56A7C10 were found to be conformational. The epitope of MA-42A2F6 comprises residues Lys(243) and Glu(350), whereas the epitope of MA-56A7C10 comprises residues Glu(242), Lys(243), Glu(244), Glu(350), Asp(355), and Arg(356). The participation of Glu(350), Asp(355), and Arg(356) provides a molecular explanation for the differential exposure of this epitope in the different conformations of PAI-1 and for the effect of these antibodies on the kinetics of the formation of the initial PAI-1-proteinase complexes. The localization of the epitopes of MA-44E4, MA42A2F6, and MA-56A7C10 elucidates two previously unidentified molecular mechanisms to modulate PAI-1 activity and opens new perspectives for the rational development of PAI-1 neutralizing compounds.     

Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy

Background

In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated.

Methods

In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed.

Results

Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05).

Conclusions

LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy.     

Graphical exploration of gene expression data: a comparative study of three multivariate methods

This article describes three multivariate projection methods and compares them for their ability to identify clusters of biological samples and genes using real-life data on gene expression levels of leukemia patients. It is shown that principal component analysis (PCA) has the disadvantage that the resulting principal factors are not very informative, while correspondence factor analysis (CFA) has difficulties interpreting distances between objects. Spectral map analysis (SMA) is introduced as an alternative approach to the analysis of microarray data. Weighted SMA outperforms PCA, and is at least as powerful as CFA, in finding clusters in the samples, as well as identifying genes related to these clusters. SMA addresses the problem of data analysis in microarray experiments in a more appropriate manner than CFA, and allows more flexible weighting to the genes and samples. Proper weighting is important, since it enables less reliable data to be down-weighted and more reliable information to be emphasized.