Investigating the role of calcium in the biomechanical response of neutrophils to mechanical deformation experienced in the pulmonary capillaries

Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006.Includes bibliographical references (p. 73-79).Neutrophils in the pulmonary microcirculation are subjected to mechanical deformation while traveling through capillaries of sizes much smaller than the mean neutrophil diameter. This deformation has been shown to result in significant reductions in both the shear storage and shear loss moduli of the cell, with subsequent recovery towards their initial values. Also, deformation above a threshold stimulus results in neutrophil activation, evidenced by pseudopod projection from the cell. These two events are thought to occur via independent pathways, yet little is known about the mechanosensing signaling involved. Other work has demonstrated that physiological deformation of neutrophils induces a marked increase in the levels of cytosolic calcium, suggesting that this occurrence may trigger the biomechanical response observed in the cell. The aim of this thesis was to elucidate the role of calcium in the neutrophil response to the mechanical deformation experienced during transit through the pulmonary capillaries.(cont.) Chelating intracellular calcium in neutrophils resulted in (i) decreased deformability of the cells into a microchannel, (ii) attenuation of the drop in shear storage modulus (G') observed in untreated cells upon deformation, and (iii) shorter activation times. These findings suggest that cytosolic calcium holds an important function in the neutrophil transit through the capillaries, and inhibition of normal calcium release within the cell can lead to leukostasis-like conditions.by Jeffrey J Hsu.M.Eng

Monomorphic Ventricular Arrhythmias in Athletes.

Ventricular arrhythmias are challenging to manage in athletes with concern for an elevated risk of sudden cardiac death (SCD) during sports competition. Monomorphic ventricular arrhythmias (MMVA), while often benign in athletes with a structurally normal heart, are also associated with a unique subset of idiopathic and malignant substrates that must be clearly defined. A comprehensive evaluation for structural and/or electrical heart disease is required in order to exclude cardiac conditions that increase risk of SCD with exercise, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Unique issues for physicians who manage this population include navigating athletes through the decision of whether they can safely continue their chosen sport. In the absence of structural heart disease, therapies such as radiofrequency catheter ablation are very effective for certain arrhythmias and may allow for return to competitive sports participation. In this comprehensive review, we summarise the recommendations for evaluating and managing athletes with MMVA

Randomized trial of conventional transseptal needle versus radiofrequency energy needle puncture for left atrial access (the TRAVERSE-LA study).

BackgroundTransseptal puncture is a critical step in achieving left atrial (LA) access for a variety of cardiac procedures. Although the mechanical Brockenbrough needle has historically been used for this procedure, a needle employing radiofrequency (RF) energy has more recently been approved for clinical use. We sought to investigate the comparative effectiveness of an RF versus conventional needle for transseptal LA access.Methods and resultsIn this prospective, single-blinded, controlled trial, 72 patients were randomized in a 1:1 fashion to an RF versus conventional (BRK-1) transseptal needle. In an intention-to-treat analysis, the primary outcome was time required for transseptal LA access. Secondary outcomes included failure of the assigned needle, visible plastic dilator shavings from needle introduction, and any procedural complication. The median transseptal puncture time was 68% shorter using the RF needle compared with the conventional needle (2.3 minutes [interquartile range {IQR}, 1.7 to 3.8 minutes] versus 7.3 minutes [IQR, 2.7 to 14.1 minutes], P = 0.005). Failure to achieve transseptal LA access with the assigned needle was less common using the RF versus conventional needle (0/36 [0%] versus 10/36 [27.8%], P < 0.001). Plastic shavings were grossly visible after needle advancement through the dilator and sheath in 0 (0%) RF needle cases and 12 (33.3%) conventional needle cases (P < 0.001). There were no differences in procedural complications (1/36 [2.8%] versus 1/36 [2.8%]).ConclusionsUse of an RF needle resulted in shorter time to transseptal LA access, less failure in achieving transseptal LA access, and fewer visible plastic shavings

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease.BackgroundThe prognostic significance of renal artery calcified plaque (RAC) and its relationship with renal function, albuminuria, and systemic atherosclerosis are unknown.MethodsCalcified atherosclerotic plaque was measured in the renal arteries of 96 unrelated Caucasian subjects with type 2 diabetes mellitus (DM) using four-channel multidetector–row computed tomography (MDCT4). Renal artery calcium was measured as the sum of ostial and main renal artery calcium scores. Participants also underwent MDCT scanning to measure coronary artery calcium (CAC), carotid artery calcium, common iliac artery calcium, infra-renal aorta calcium, and B-mode ultrasound to measure carotid artery intima-medial thickness (IMT). Spearman's rank correlation coefficients were used to assess associations between RAC and measures of subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, gender, body mass index (BMI), DM duration, smoking, and serum cholesterol and triglyceride levels.ResultsCharacteristics of the study group were 54% (52/96) female with a mean ± SD (median) age 62.8 ± 8.4 (62.5) years, DM duration 10.6 ± 6.3 (8.0) years, hemoglobin A1C 7.5 ± 1.5 (7.2)%, BMI 32.1 ± 6.3 (31.1) kg/m2, serum creatinine concentration 1.11 ± 0.18 (1.10) mg/dL, urine albumin:creatinine ratio (ACR) 105.3 ± 423.1 (17.6) mg/g, modified MDRD equation glomerular filtration rate (GFR) 64.3 ± 12.6 (63.6) mL/min, RAC 372 ± 799 (101), CAC 1819 ± 2594 (622), carotid artery calcium 264 ± 451 (72), and B-mode ultrasound carotid IMT 0.70 ± 0.12 (0.69) mm. Sixty-five percent of subjects (62/96) had detectable RAC. Renal artery calcium was significantly associated with CAC (r = 0.50, P < 0.0001), carotid artery calcium (r = 0.58, P < 0.0001), common iliac artery calcium (r = 0.45, P < 0.0001), infra-renal aorta calcium (r = 0.70, P < 0.0001), IMT (r = 0.40, P = 0.0004), diastolic blood pressure (r=-0.33, P = 0.0009), BMI (r=-0.19, P = 0.0573), and age (r = 0.54, P < 0.0001). There was no association between RAC and GFR (r=-0.15, P = 0.1637) or between RAC and urine ACR (r = 0.07, P = 0.5083).ConclusionRenal artery calcium is strongly associated with older age, diastolic blood pressure, BMI, carotid artery IMT, and coronary, carotid, common iliac artery, and infra-renal aorta calcium in Caucasians with type 2 diabetes mellitus. Renal artery calcium, similar to CAC and IMT, appears to be a useful noninvasive marker of subclinical atherosclerosis. However, RAC is not significantly associated with either GFR or albuminuria

Advanced microscopy to elucidate cardiovascular injury and regeneration: 4D light-sheet imaging

The advent of 4-dimensional (4D) light-sheet fluorescence microscopy (LSFM) has provided an entry point for rapid image acquisition to uncover real-time cardiovascular structure and function with high axial resolution and minimal photo-bleaching/-toxicity. We hereby review the fundamental principles of our LSFM system to investigate cardiovascular morphogenesis and regeneration after injury. LSFM enables us to reveal the micro-circulation of blood cells in the zebrafish embryo and assess cardiac ventricular remodeling in response to chemotherapy-induced injury using an automated segmentation approach. Next, we review two distinct mechanisms underlying zebrafish vascular regeneration following tail amputation. We elucidate the role of endothelial Notch signaling to restore vascular regeneration after exposure to the redox active ultrafine particles (UFP) in air pollutants. By manipulating the blood viscosity and subsequently, endothelial wall shear stress, we demonstrate the mechanism whereby hemodynamic shear forces impart both mechanical and metabolic effects to modulate vascular regeneration. Overall, the implementation of 4D LSFM allows for the elucidation of mechanisms governing cardiovascular injury and regeneration with high spatiotemporal resolution

Advanced microscopy to elucidate cardiovascular injury and regeneration: 4D light-sheet imaging

The advent of 4-dimensional (4D) light-sheet fluorescence microscopy (LSFM) has provided an entry point for rapid image acquisition to uncover real-time cardiovascular structure and function with high axial resolution and minimal photo-bleaching/-toxicity. We hereby review the fundamental principles of our LSFM system to investigate cardiovascular morphogenesis and regeneration after injury. LSFM enables us to reveal the micro-circulation of blood cells in the zebrafish embryo and assess cardiac ventricular remodeling in response to chemotherapy-induced injury using an automated segmentation approach. Next, we review two distinct mechanisms underlying zebrafish vascular regeneration following tail amputation. We elucidate the role of endothelial Notch signaling to restore vascular regeneration after exposure to the redox active ultrafine particles (UFP) in air pollutants. By manipulating the blood viscosity and subsequently, endothelial wall shear stress, we demonstrate the mechanism whereby hemodynamic shear forces impart both mechanical and metabolic effects to modulate vascular regeneration. Overall, the implementation of 4D LSFM allows for the elucidation of mechanisms governing cardiovascular injury and regeneration with high spatiotemporal resolution