Glomerular filtration and podocyte tensional homeostasis: importance of the minor type IV collagen network.

The minor type IV collagen chain, which is a significant component of the glomerular basement membrane in healthy individuals, is known to assemble into large structures (supercoils) that may contribute to the mechanical stability of the collagen network and the glomerular basement membrane as a whole. The absence of the minor chain, as in Alport syndrome, leads to glomerular capillary demise and eventually to kidney failure. An important consideration in this problem is that the glomerular capillary wall must be strong enough to withstand the filtration pressure and porous enough to permit filtration at reasonable pressures. In this work, we propose a coupled feedback loop driven by filtration demand and tensional homeostasis of the podocytes forming the outer portion of the glomerular capillary wall. Briefly, the deposition of new collagen increases the stiffness of basement membrane, helping to stress shield the podocytes, but the new collagen also decreases the permeability of the basement membrane, requiring an increase in capillary transmural pressure drop to maintain filtration; the resulting increased pressure outweighs the increased glomerular basement membrane stiffness and puts a net greater stress demand on the podocytes. This idea is explored by developing a multiscale simulation of the capillary wall, in which a macroscopic (µm scale) continuum model is connected to a set of microscopic (nm scale) fiber network models representing the collagen network and the podocyte cytoskeleton. The model considers two cases: healthy remodeling, in which the presence of the minor chain allows the collagen volume fraction to be increased by thickening fibers, and Alport syndrome remodeling, in which the absence of the minor chain allows collagen volume fraction to be increased only by adding new fibers to the network. The permeability of the network is calculated based on previous models of flow through a fiber network, and it is updated for different fiber radii and volume fractions. The analysis shows that the minor chain allows a homeostatic balance to be achieved in terms of both filtration and cell tension. Absent the minor chain, there is a fundamental change in the relation between the two effects, and the system becomes unstable. This result suggests that mechanobiological or mechanoregulatory therapies may be possible for Alport syndrome and other minor chain collagen diseases of the kidney.

Cell-matrix interaction during strain-dependent remodelling of simulated collagen networks.

The importance of tissue remodelling is widely accepted, but the mechanism by which the remodelling process occurs remains poorly understood. At the tissue scale, the concept of tensional homeostasis, in which there exists a target stress for a cell and remodelling functions to move the cell stress towards that target, is an important foundation for much theoretical work. We present here a theoretical model of a cell in parallel with a network to study what factors of the remodelling process help the cell move towards mechanical stability. The cell-network system was deformed and kept at constant stress. Remodelling was modelled by simulating strain-dependent degradation of collagen fibres and four different cases of collagen addition. The model did not lead to complete tensional homeostasis in the range of conditions studied, but it showed how different expressions for deposition and removal of collagen in a fibre network can interact to modulate the cell's ability to shield itself from an imposed stress by remodelling the surroundings. This study also showed how delicate the balance between deposition and removal rates is and how sensitive the remodelling process is to small changes in the remodelling rules.

Effect of Supercoiling on the Mechanical and Permeability Properties of Model Collagen IV Networks.

Collagen IV networks in the glomerular basement membrane (GBM) are essential for the maintenance and regulation of blood filtration in the kidneys. The GBM contains two different types of collagen IV networks: [α1(IV)]2α2(IV) and α3(IV)α4(IV)α5(IV), the latter of which has a higher number of supercoils (two or more collagens coiling around each other). To investigate the effects of supercoiling on the mechanical and permeability properties of collagen IV networks, we generated model collagen IV networks in the GBM and reconnected them to create different levels of supercoiling. We found that supercoiling greatly increases the stiffness of collagen IV networks but only minimally decreases the permeability. Also, doubling the amount of supercoils in a network had a bigger effect than doubling the stiffness of the supercoils. Our results suggest that the formation of supercoils is a specialized mechanism by the GBM that provides with a network stiff and strong enough to withstand the high hydrostatic pressures of filtration, yet porous enough that filtration is not hindered. Clinically, understanding the effects of supercoiling gives us insight into the mechanisms of GBM failure in some disease states where the normal collagen IV structure is disrupted.

Impact of mitral valve geometry on hemodynamic efficacy of surgical repair in secondary mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: Mitral valve geometry is significantly altered secondary to left ventricular remodeling in non-ischemic and ischemic dilated cardiomyopathies. Since the extent of remodeling and asymmetry of dilatation of the ventricle differ significantly between individual patients, the valve geometry and tethering also differ. The study aim was to determine if mitral valve geometry has an impact on the efficacy of surgical repairs to eliminate regurgitation and restore valve closure in a validated experimental model. METHODS: Porcine mitral valves (n = 8) were studied in a pulsatile heart simulator, in which the mitral valve geometry can be precisely altered and controlled throughout the experiment. Baseline hemodynamics for each valve were measured (Control), and the valves were tethered in two distinct ways: annular dilatation with 7 mm apical papillary muscle (PM) displacement (Tether 1, symmetric), and annular dilatation with 7 mm apical, 7 mm posterior and 7 mm lateral PM displacement (Tether 2, asymmetric). Mitral annuloplasty was performed on each valve (Annular Repair), succeeded by anterior leaflet secondary chordal cutting (Sub-annular Repair). The efficacy of each repair in the setting of a given valve geometry was quantified by measuring the changes in mitral regurgitation (MR), leaflet coaptation length, tethering height and area. RESULTS: At baseline, none of the valves was regurgitant. Significant leaflet tethering was measured in Tether 2 over Tether 1, but both groups were significantly higher compared to baseline (60.9 +/- 31 mm2 for Control versus 129.7 +/- 28.4 mm2 for Tether 1 versus 186.4 +/- 36.3 mm2 for Tether 2). Consequently, the MR fraction was higher in Tether 2 group (23.0 +/- 5.7%) than in Tether 1 (10.5 +/- 5.5%). Mitral annuloplasty reduced MR in both groups, but remnant regurgitation after the repair was higher in Tether 2. After chordal cutting a similar trend was observed with trace regurgitation in Tether 1 group at 3.6 +/- 2.8%, in comparison to 18.6 +/- 4.2% in the Tether 2 group. CONCLUSION: In this experimental model, the tethering geometry of the mitral valve impacts the valve hemodynamics after annuloplasty and chordal cutting. The quantitative assessment of valve geometry may help in tailoring a repair to the specific tethering pattern.

Mechanical response of wild-type and Alport murine lens capsules during osmotic swelling.

The mechanical support of basement membranes, such as the lens capsule, is believed to arise from one of their main constituents - collagen IV. The basement membranes of the lens, kidney, and ear normally contain two different types of collagen IV networks, referred to as the major and minor chain networks. In Alport syndrome, a mutation in one of the minor chain COL4 genes leads to the absence of the minor chain network, causing life-threatening disturbances. We hypothesized that the absence of the minor chain network increases basement membrane distensibility, as measured in wild-type (n = 25) and Alport syndrome (n = 21) mice using the lens capsule as a model. Osmotic swelling experiments revealed direction-dependent changes. As a reflection of lens capsule properties, Alport lenses strained significantly more than wild-type lenses in the anterior-posterior direction, i.e. along their thickness, but not in the equatorial direction (p = 0.03 and p = 0.08, respectively). This is consistent with clinical data: Alport patients develop conical protrusions on the anterior and posterior lenticular poles. There was no evidence of significant change in total amount of collagen between Alport and wild-type lenses (p = 0.6). The observed differences in distensibility could indicate that the major chain network alone cannot fully compensate for the absence of the more highly cross-linked minor chain network, which is believed to be stronger, more stable, and resistant to deformation. The addition of mechanical information on Alport syndrome to the currently available biological data provides a fuller picture into the progression of the disease.

Comparison of artificial neochordae and native chordal transfer in the repair of a flail posterior mitral leaflet: an experimental study.

BACKGROUND: Surgical reconstruction of a flail posterior leaflet is a routine mitral valve repair, the techniques for which have evolved from leaflet resection to leaflet preservation. Artificial expanded polytetrafluoroethylene neochordae are frequently used to stabilize the flail leaflet and seldom, translocation of the native secondary chordae of the valve to the leaflet free edge is used. In this study, we sought to investigate the efficacy of the 2 techniques to correct posterior leaflet prolapse and reduce mitral regurgitation, and quantify the acute post repair leaflet kinematics. METHODS: Adult porcine mitral valves (n =7) were studied in a pulsatile left heart experimental model in which isolated P2 flail was mimicked by marginal chordal transection. Baseline conditions were established in each valve under normal conditions (control) and were followed by induction of isolated P2 flail by transecting the 2 marginal chordae on the posterior leaflet free edge (disease). The flail posterior leaflet was reconstructed using artificial neochordae (repair 1) and then native chordal translocation (repair 2). Reduction in leaflet flail, changes in mitral regurgitation fraction, leaflet coaptation length, and posterior leaflet mobility were measured using B-mode echocardiography or color Doppler. RESULTS: At baseline, all the valves were competent with no mitral regurgitation. After transection of the marginal chordae on the posterior leaflet, isolated P2 flail was evident with 13.7% ± 13% regurgitation. Reconstruction with artificial neochordae eliminated leaflet flail and reduced mitral regurgitation to 3.2% ± 2.8%, and with chordal translocation leaflet flail was corrected and mitral regurgitation was measured at 2.3% ± 2.6%. Using either repair techniques, leaflet coaptation and mobility of the repaired leaflets were adequate and comparable with the baseline measurements. CONCLUSIONS: Comparable reduction leaflet flail and regurgitation, and restoration of physiologic leaflet coaptation with the 2 techniques indicate that under acute conditions, use of artificial neochordae or native chordal translocations have similar benefits.

Effect of anterior strut chordal transection on the force distribution on the marginal chordae of the mitral valve.

OBJECTIVES: Transection of the secondary chordae on the anterior leaflet of the mitral valve to relieve leaflet tethering and reduce regurgitation is an experimentally proven procedure to correct functional mitral regurgitation. In the present study, we sought to investigate whether transecting the secondary chordae would have an effect on the marginal chordal force on the same leaflet. METHODS: Adult porcine mitral valves (n = 8) were studied in a pulsatile heart simulator, in which the papillary muscle positions can be precisely positioned. Miniature transducers were inserted into the anterior marginal chordae to measure the chordal forces. Each valve was studied under baseline conditions, 3 different tethering conditions (apical, apical-lateral, and apical-lateral-posterior), and after chordal cutting in the 3 tethering conditions. The temporal changes and peak and average marginal chordal forces under each condition are reported. RESULTS: Apical tethering increased the marginal chordal force by an average of 96% but remained unchanged after chordal cutting. With apical-lateral tethering, the marginal chordal force increased by 210% from baseline and increased further to 350% of baseline after chordal cutting. After apical-lateral-posterior tethering, the marginal chordal force increased to 335% of baseline before transection and by 548% after transection. CONCLUSIONS: The increase in the marginal chordal force after secondary chordal cutting depends on the location of the papillary muscles and the extent of leaflet tethering. Although chordal cutting might not alter the valve mechanics under minimal leaflet tethering, it significantly affects the mechanics when the leaflet tethering is more pronounced, which is typically seen in patients with functional mitral regurgitation.