Inducing persistent flow disturbances accelerates atherogenesis and promotes thin cap fibroatheroma development in D374Y-PCSK9 hypercholesterolemic minipigs

BACKGROUND: -Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma (TCFA). METHODS AND RESULTS: -D374Y-PCSK9 hypercholesterolemic minipigs (N=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately post-stent, 19, and 34 weeks and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially-collected histological sections and co-registered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ~3-fold higher downstream of the SMS compared to both upstream of the SMS and in the control artery (p<0.001). Advanced plaques were also primarily observed downstream of the SMS, in locations initially exposed to both low (p<0.002) and multidirectional (p<0.002) shear stress. TCFA regions demonstrated significantly lower shear stress that persisted over the duration of the study compared to other plaque types (p<0.005). CONCLUSIONS: -These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of TCFA

Radiolaria and Phaeodaria

Polycystina (~400–800 living species and several thousand extinct forms) and Phaeodaria (~400–500 living species) are exclusively marine, open-ocean planktonic protists, most of which possess elaborate siliceous skeletons. The cytoplasm is divided into an internal part (endoplasm) separated from the external, more vacuolated one (ectoplasm) by a perforated membrane – the central capsule. The Polycystina protrude long and slender cytoplasmic projections (axopodia) supported internally by a rigid central rod (axoneme); while the Phaeodria have anetwork ofperipheral finely interconnectedpseudopodia.Afew Polycystina are colonial, but most, as well as all Phaeodaria, are solitary, around 40 μm to almost 2 mm in size. Most polycystine species peak in abundance between 0 and 100 m, whereasphaeodarianstendtolivedeeper,oftenbelow300m.Polycystineshavea rich fossil record dating from the Cambrian and are important for stratigraphic, paleoecologic, and evolutionary studies. The world-wide biogeography and diversity of radiolarians is chiefly governed by water temperature. Radiolarian prey includes bacteria, algae, protozoa, and microinvertebrates. Many surfacedwelling species of Polycystina possess symbiotic algae and photosynthetic cyanobacteria that provide nourishment to the host. Some colonial radiolaria reproduce by binary fission of the central capsules. Sexual reproduction of polycystines or Phaeodaria has not been confirmed, but the release of motile swarmers, likely gametes, has been widely documented. In species with a radial symmetry (Spumellaria) shell-growth is centrifugal, whereas in the Nassellaria the internal cephalic elements and the cephalis appear first. Individual longevity is estimated to range between 2 and 3 weeks and 1–2 months