Cardiology

Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. Depression scores after treatment and adverse effects. Ten publications reporting on 14 trials (6262 participants) were included: ...

The Grenada Heart Project aims to study the clinical, biological, and psychosocial determinants of the cardiovascular health in Grenada in order to develop and implement a nationwide cardiovascular health promotion program. We recruited 2,827 adults randomly selected from the national electronic voter list. The main outcome measures were self-reported cardiovascular disease and behavioral risk factors, anthropometric measures, blood pressure, point-of-care testing for glucose and lipids, and ankle-brachial index. Risk factors were also compared with the U.S. National Health and Nutritional Survey data. Prevalence of cardiovascular disease risk factors were: overweight and obesity-57.7% of the population, physical inactivity-23.4%, diabetes-13.3%, hypertension-29.7%, hypercholesterolemia-8.6%, and smoking-7%. Subjects who were physically active had a significantly lower 10-year Framingham risk score (p<0.001). Compared with the U.S. National Health and Nutrition Survey data, Grena...

O B J E C T I V E The Grenada Heart Project aims to study the clinical, biological, and psychosocial determinants of the cardiovascular health in Grenada in order to develop and implement a nationwide cardiovascular health promotion program.

Category: Appropriateness, Pay for Performance, Cost of Care Background: Some recent major cardiovascular (CV) trials have been faulted for utilizing surrogate instead of clinical endpoints. Selection of surrogate endpoints is thought to be driven by financial factors-smaller sample size, shorter follow up, and a potentially larger effect. It remains unknown whether sponsorship/funding source of major cardiovascular trials published in high impact journals influences the choice of clinical vis-avis surrogate endpoints for primary outcomes. In addition, the frequency of safety endpoints has not been previously reported in CV trials.

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebocontrolled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.974.35 mg/day) was superior to placebo in the treatment of repetitive behaviors by CY-BOCS compulsion scale. The effect size was in the moderate to large range, and the doses used were low. Liquid fluoxetine was only slightly, and not significantly, superior to placebo on CGI autism score partially due to a phase order effect. However, fluoxetine was marginally superior to placebo on a composite measure of global effectiveness. Liquid fluoxetine did not significantly differ from placebo on treatment emergent side effects. Liquid fluoxetine in low doses is more effective than placebo in the treatment of repetitive behaviors in childhood autism. Limitations include small sample size and the crossover design of the study. Further replication and long-term maintenance trials are needed.

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.9+/-4.35 mg/day) was superior to placebo in the t...

In this study, bone cells were successfully cultured into a micropatterned network with dimensions close to that of in vivo osteocyte networks using microcontact printing and self-assembled monolyers (SAMs). The optimal geometric parameters for the formation of these networks were determined in terms of circle diameters and line widths. Bone cells patterned in these networks were also able to form gap junctions with each other, shown by immunofluorescent staining for the gap junction protein connexin 43, as well as the transfer of gap-junction permeable calcein-AM dye. We have demonstrated for the first time, that the intracellular calcium response of a single bone cell indented in this bone cell network, can be transmitted to neighboring bone cells through multiple calcium waves. Furthermore, the propagation of these calcium waves was diminished with increased cell separation distance. Thus, this study provides new experimental data that support the idea of osteocyte network memory of mechanical loading similar to memory in neural networks.

To study how the dynamic subcellular mechanical properties of the heart relate to the fundamental underlying process of actin-myosin cross-bridge cycling, we developed a novel atomic force microscope elastography technique for mapping spatiotemporal stiffness of isolated, spontaneously beating neonatal rat cardiomyocytes. Cells were indented repeatedly at a rate close but unequal to their contractile frequency. The resultant changes in pointwise apparent elastic modulus cycled at a predictable envelope frequency between a systolic value of 26.2 ± 5.1 kPa and a diastolic value of 7.8 ± 4.1 kPa at a representative depth of 400 nm. In cells probed along their major axis, spatiotemporal changes in systolic stiffness displayed a heterogeneous pattern, reflecting the banded sarcomeric structure of underlying myofibrils. Treatment with blebbistatin eliminated contractile activity and resulted in a uniform apparent modulus of 6.5 ± 4.8 kPa. This study represents the first quantitative dynam...

With relatively high frame rates and the ability to acquire volume data sets with a stationary transducer, 3D ultrasound systems, based on matrix phased array transducers, provide valuable three-dimensional information, from which quantitative measures of cardiac function can be extracted. Such analyses require segmentation and visual tracking of the left ventricular endocardial border. Due to the large size of the volumetric data sets, manual tracing of the endocardial border is tedious and impractical for clinical applications. Therefore the development of automatic methods for tracking three-dimensional endocardial motion is essential. In this study, we evaluate a four-dimensional optical flow motion tracking algorithm to determine its capability to follow the endocardial border in three dimensional ultrasound data through time. The four-dimensional optical flow method was implemented using three-dimensional correlation. We tested the algorithm on an experimental open-chest dog data set and a clinical data set acquired with a Philips' iE33 three-dimensional ultrasound machine. Initialized with left ventricular endocardial data points obtained from manual tracing at end-diastole, the algorithm automatically tracked these points frame by frame through the whole cardiac cycle. Finite element surfaces were fitted through the data points obtained by both optical flow tracking and manual tracing by an experienced observer for quantitative comparison of the results. Parameterization of the finite element surfaces was performed and maps displaying relative differences between the manual and semi-automatic methods were compared. The results showed good consistency with less than 10% difference between manual tracing and optical flow estimation on 73% of the entire surface. In addition, the optical flow motion tracking algorithm greatly reduced processing time (about 94% reduction compared to human involvement per cardiac cycle) for analyzing cardiac function in threedimensional ultrasound data sets. A displacement field was computed from the optical flow output, and a framework for computation of dynamic cardiac information is introduced. The method was applied to a clinical data set from a heart transplant patient and dynamic measurements agreed with known physiology as well as experimental results.

Structural and mechanical anisotropy are critical to the function of many engineered tissues. This study examined the ability of anisotropic tissue constructs to overcome contact guidance cues and remodel in response to altered mechanical loading conditions. Square tissues engineered from dermal fibroblasts and type-I collagen were uniaxially loaded to induce cell and matrix alignment. After an initial time, t*, of 5 to 72 hrs, loading was switched from the x-axis to the y-axis. Cell alignment was examined throughout the experiment until a steady state was reached. Before t*, cells spontaneously aligned in the x-direction. After t*, the strength of alignment transiently decreased then increased, and mean cell orientation transitioned from the x-to the y-direction following an exponential time course with a time constant that increased with t*. Collagen fiber orientation exhibited similar trends that could not be explained by passive kinematics alone. Structural realignment resulted in concomitant changes in biaxial tissue mechanical properties. The findings suggest that even highly aligned engineered tissue constructs retain the capacity to remodel in response to altered mechanical stimuli. This may have important functional consequences when an anisotropic engineered tissue designed in vitro is surgically implanted into a mechanically complex graft site.

Background. The global left ventricular dysfunction characteristic of left ventricular aneurysm is associated with muscle fiber stretching in the adjacent noninfarcted (border zone) region during isovolumic systole. The mechanism of this regional dysfunction is poorly understood. Methods. An anteroapical transmural myocardial infarct was created by coronary arterial ligation in an adult Dorset sheep and was allowed to mature into left ventricular aneurysm for 10 weeks. The animal was imaged subsequently using magnetic resonance imaging with simultaneous recording of intraventricular pressures. A realistic mathematical model of the three-dimensional ovine left ventricle with an anteroapical aneurysm was constructed from multiple short-axis and long-axis magnetic resonance imaging slices at the beginning of diastolic filling. Results. Three model simulations are presented: (1) normal border zone contractility and normal aneurysmal material properties; (2) greatly reduced border zone contractility (by 50%) and normal aneurysmal material properties; and (3) greatly reduced border zone contractility (by 50%) and stiffened aneurysmal material properties (by 1000%). Only the latter two simulations were able to reproduce experimentally observed stretching of border zone fibers during isovolumic systole. Conclusions. The mechanism underlying mechanical dysfunction in the border zone region of left ventricular aneurysm is primarily the result of myocardial contractile dysfunction rather than increased wall stress in this region.

Human (h) pluripotent stem cells (PSC) such as embryonic stem cells (ESC) can be directed into cardiomyocytes (CMs), representing a potential unlimited cell source for disease modeling, cardiotoxicity screening and myocardial repair. Although the electrophysiology of single hESC-CMs is now better defined, their multi-cellular arrhythmogenicity has not been thoroughly assessed due to the lack of a suitable experimental platform. Indeed, the generation of ventricular (V) fibrillation requires single-cell triggers as well as sustained multi-cellular reentrant events. Although native VCMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions, hESC-derived CM (hESC-CM) clusters are heterogenous and randomly organized, and therefore not representative of native conditions. Here, we reported that engineered alignment of hESC-VCMs on biomimetic grooves uniquely led to physiologically relevant responses. Aligned but not isotropic control preparations showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resembling the native human V anisotropic ratio (AR ¼ LCV/TCV ¼ 1.8e2.0). Importantly, the total incidence of spontaneous and inducible arrhythmias significantly reduced from 57% in controls to 17e23% of aligned preparations, thereby providing a physiological baseline for assessing arrhythmogenicity. As such, promotion of pro-arrhythmic effect (e.g., spatial dispersion by b adrenergic stimulation) could be better predicted. Mechanistically, such anisotropy-induced electrical stability was not due to maturation of the cellular properties of hESC-VCMs but their physical arrangement. In conclusion, not only do functional anisotropic hESC-VCMs engineered by multi-scale topography represent a more accurate model for efficacious drug discovery and development as well as arrhythmogenicity screening (of pharmacological and genetic factors), but our approach may also lead to future transplantable prototypes with improved efficacy and safety against arrhythmias.

Because of the avascular nature of adult cartilage nutrients and waste products are transported to and from the chondrocytes by diffusion and convection through the extracellular matrix. The convective interstitial fluid flow within and around chondrocytes is poorly understood. This theoretical study demonstrates that the incorporation of a semi-permeable membrane when modeling the chondrocyte leads to the following findings: Under mechanical loading of an isolated chondrocyte the intracellular fluid pressure is on the order of tens of Pascals and the transmembrane fluid outflow, on the order of picometers per second, takes several days to subside; consequently the chondrocyte behaves practically as an incompressible solid whenever the loading duration is on the order of minutes or hours. When embedded in its extracellular matrix, the chondrocyte response is substantially different. Mechanical loading of the tissue leads to a fluid pressure difference between intracellular and extracellular compartments on the order of tens of kilopascals and the transmembrane outflow, on the order of a nanometer per second, subsides in about one hour. The volume of the chondrocyte decreases concomitantly with that of the extracellular matrix. The interstitial fluid flow in the extracellular matrix is directed around the cell, with peak values on the order of tens of nanometers per second. The viscous fluid shear stress acting on the cell surface is orders of magnitude smaller than the solid matrix shear stresses resulting from the extracellular matrix deformation. These results provide new insight toward our understanding of water transport in chondrocytes.

Misfolding and aggregation of the amyloid b-protein (Ab) are hallmarks of Alzheimer's disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu 2þ. Cu 2þ cations regulate early stages of Ab aggregation, but the molecular mechanism of Cu 2þ regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu 2þ cations on interpeptide interactions. By immobilizing one of two interacting Ab42 molecules on a mica surface and tethering the counterpart molecule onto the tip, we were able to probe the interpeptide interactions in the presence and absence of Cu 2þ cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu 2þ cations change the pattern of Ab interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu 2þ cations induce Ab42 peptide structural changes resulting in N-termini interactions within the dimers. Cu 2þ cations also stabilize the dimers. No effects of Cu 2þ cations on Ab-Ab interactions were observed at pH4.0, suggesting that peptide protonation changes the peptide-cation interaction. The effect of Cu 2þ cations on later stages of Ab aggregation was studied by AFM topographic images. The results demonstrate that substoichiometric Cu 2þ cations accelerate the formation of fibrils at pH 7.4 and 5.0, whereas no effect of Cu 2þ cations was observed at pH 4.0. Taken together, the combined AFM force spectroscopy and imaging analyses demonstrate that Cu 2þ cations promote both the initial and the elongation stages of Ab aggregation, but protein protonation diminishes the effect of Cu 2þ .

The purpose of our study was to determine the influence of cinacalcet on bone markers such as tartrate resistant acid phosphatase TRAP5b and iPTH in management of secondary hyperparathyroidism. Methods: We studied group of 22 patients with sHPT with PTHN 450 pg/ml (mean 757± 264 pg/ml) (F =10, M=12; peritoneal dialysis 5 patients and hemodialysis 17 patients; mean age 59±17). There were 2 subgroups of patients with sHPT: group A treated with cinacalcet and group B treated with traditional methods (calcium carbonate and alphacalcidol). The following parameters were determined in serum: iPTH, Ca, P and tartrate resistant acid phosphatase TRACP5b as a marker of bone resorption. TRACP 5b activity was measured using assay Bone TRAP™ (SBA Finland). Intact PTH was measured using immunoradiometric assay (Diasorin USA). These parameters were measured before the start of cinacalcet therapy and after the 3rd and 6th months of therapy. Results: Patients treated with cinacalcet (group A) had significant lower values of iPTH and TRAP 5b after the 3rd and 6th months of therapy in comparison to group B. We observed 61%/67% respectively reduction of iPTH level and 82%/76% reduction of TRAP 5b level. We did not find any significant difference between examined parameters in group B. Conclusion: Treatment of secondary hyperparathyroidism with cinacalcet in dialysed patients was effective and allowed the significant reductions of iPTH and TRACP 5b levels. Monitoring of TRACP5b might be useful in assessment of bone resorption in the course of cinacalcet treatment.