Simulation of early calcific aortic valve disease in a 3D platform: A role for myofibroblast differentiation.

PURPOSE: Calcific aortic valve disease (CAVD) is the most prevalent valve disease in the Western world. Recent difficulty in translating experimental results on statins to beneficial clinical effects warrants the need for understanding the role of valvular interstitial cells (VICs) in CAVD. In two-dimensional culture conditions, VICs undergo spontaneous activation similar to pathological differentiation, which intrinsically limits the use of in vitro models to study CAVD. Here, we hypothesized that a three-dimensional (3D) culture system based on naturally derived extracellular matrix polymers, mimicking the microenvironment of native valve tissue, could serve as a physiologically relevant platform to study the osteogenic differentiation of VICs. PRINCIPAL RESULTS: Aortic VICs loaded into 3D hydrogel constructs maintained a quiescent phenotype, similar to healthy human valves. In contrast, osteogenic environment induced an initial myofibroblast differentiation (hallmarked by increased alpha smooth muscle actin [α-SMA] expression), followed by an osteoblastic differentiation, characterized by elevated Runx2 expression, and subsequent calcific nodule formation recapitulating CAVD conditions. Silencing of α-SMA under osteogenic conditions diminished VIC osteoblast-like differentiation and calcification, indicating that a VIC myofibroblast-like phenotype may precede osteogenic differentiation in CAVD. MAJOR CONCLUSIONS: Using a 3D hydrogel model, we simulated events that occur during early CAVD in vivo and provided a platform to investigate mechanisms of CAVD. Differentiation of valvular interstitial cells to myofibroblasts was a key mechanistic step in the process of early mineralization. This novel approach can provide important insight into valve pathobiology and serve as a promising tool for drug screening.

Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease.

Chronic renal disease (CRD) accelerates the development of atherosclerosis. The potent protease cathepsin S cleaves elastin and generates bioactive elastin peptides, thus promoting vascular inflammation and calcification. We hypothesized that selective cathepsin S inhibition attenuates atherogenesis in hypercholesterolemic mice with CRD. CRD was induced by 5/6 nephrectomy in high-fat high-cholesterol fed apolipoprotein E-deficient mice. CRD mice received a diet admixed with 6.6 or 60 mg/kg of the potent and selective cathepsin S inhibitor RO5444101 or a control diet. CRD mice had significantly higher plasma levels of osteopontin, osteocalcin, and osteoprotegerin (204%, 148%, and 55%, respectively; P < 0.05), which were inhibited by RO5444101 (60%, 40%, and 36%, respectively; P < 0.05). Near-infrared fluorescence molecular imaging revealed a significant reduction in cathepsin activity in treated mice. RO5444101 decreased osteogenic activity. Histologic assessment in atherosclerotic plaque demonstrated that RO5444101 reduced immunoreactive cathepsin S (P < 0.05), elastin degradation (P = 0.01), plaque size (P = 0.01), macrophage accumulation (P < 0.01), growth differentiation factor-15 (P = 0.0001), and calcification (alkaline phosphatase activity, P < 0.01; osteocalcin, P < 0.05). Furthermore, cathepsin S inhibitor or siRNA significantly decreased expression of growth differentiation factor-15 and monocyte chemotactic protein-1 in a murine macrophage cell line and human primary macrophages. Systemic inhibition of cathepsin S attenuates the progression of atherosclerotic lesions in 5/6 nephrectomized mice, serving as a potential treatment for atherosclerosis in patients with CRD.

Impact of right ventricular volumes on the outcomes of TAVR: a volumetric analysis of preprocedural computed tomography.

AIMS: The aim of this study was to assess the prognostic implications of increased right ventricle volume index (RVVI) using cardiac-gated computed tomography angiography (CCTA) data among patients undergoing transcatheter valve replacement (TAVR). METHODS AND RESULTS: CCTA of 323 patients who underwent TAVR at Stanford University Medical Center (CA, USA) and Tel Aviv Medical Center (Israel) between 2013 and 2016 was analysed by an automatic four-chamber volumetric software and grouped into quartiles according to RVVI. Higher one-year mortality rates were noted for the upper quartiles - 5%, 4.9%, 8.6%, and 16% (p=0.039), in Q1 <59 ml/m2, Q2 59-69 ml/m2, Q3 69-86 ml/m2, and Q4 >86 ml/m2, respectively. However, the differences were not significant after propensity score adjustments. Sub-analyses of Q1 demonstrated an escalating risk for one-year mortality in concordance to RVVI: HR 2.28, HR 2.76, and HR 4.7, for the upper 25th, 15th, and 5th percentiles, respectively (p<0.05 for all comparisons). After propensity score adjustments for clinical and echocardiographic characteristics, only the upper 5th percentiles (RVVI >120 ml/m2) retained statistical significance (HR 2.82, 95% CI: 1.02-7.78, p=0.045). Notably, 68.7% of patients from this group were considered low-intermediate risk for surgery. CONCLUSIONS: Cardiac volumetric data by CCTA performed for procedural planning may help to predict outcome in patients undergoing TAVR.

Hyalurostructure treatment: superior clinical outcome through a new protocol-a 4-year comparative study of two methods for tear trough treatment.

BACKGROUND: The tear trough represents a main aesthetic characteristic of the aging process, which leads many patients to the wish for a safe and efficient rejuvenation method to fill their eye rings. The authors analyzed results and complication rates of two methods for hollow eye ring treatment. METHODS: The authors used two methods on two patient collectives. Group A was treated using hyaluronic acid gel (Restylane; Q-Med, Uppsala, Sweden) and a reinforced 25-gauge Pix'l+ micro cannula. The authors developed a modified method for group B that included a combination of cooling of the periorbital area, no local anesthesia, preincision displacement of malar fat 10 mm below the orbital border, and postintervention corticoid therapy for 48 hours. RESULTS: Protocol B was associated with significantly lower complication rates. The authors also analyzed in how smoking, age, and skin properties might affect the clinical outcome. They found that choice of treatment and a history of blepharoplasty were significant predictive factors that correlated with complications. CONCLUSIONS: Tear trough treatment by hyalurostructure shows satisfying and efficient results with few complications. The revised technique used in group B combines multiple peri-interventional procedures including preinjection cooling of the periorbital area, preincision with displacement of the malar fat 10 mm below the orbital border, applying gentle back-and-forth movements while injecting, and oral corticosteroid therapy 48 hours after intervention. This technique makes hyalurostructure a competent and promising treatment for tear trough management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.