SummaryWhile reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF + cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

Acute type A aortic dissection is a lethal condition requiring emergency surgery. It has diverse presentations, and the diagnosis can be missed or delayed. Once diagnosed, decisions with regard to initial management, transfer, appropriateness of surgery, timing of operation, and intervention for malperfusion complications are necessary. The goals of surgery are to save life by prevention of pericardial tamponade or intra-pericardial aortic rupture, to resect the primary entry tear, to correct or prevent any malperfusion and aortic valve regurgitation, and if possible to prevent late dissection-related complications in the proximal and downstream aorta. No randomized trials of treatment or techniques have ever been performed, and novel therapies-particularly with regard to extent of surgery-are being devised and implemented, but their role needs to be defined. Overall, except in highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement. By highlighting difficulties and controversies in diagnosis, patient selection, and surgical therapy, our over-arching goal should be to enfranchise more patients for treatment and improve surgical outcomes.

Background Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to development of this condition. Methods and Results Microarrays were used to measure gene expression in 11 myxomatous and 11 non-myxomatous human mitral valves. Differential gene expression (thresholds p<0.05; fold-change>1.5) and pathway activation (Ingenuity) were confirmed using qRT-PCR and immunohistochemistry. Contributions of BMP4 and TGF-β2 to differential gene expression were evaluated in vitro. Contributions of angiotensin-II to differential pathway activation were examined in mice in vivo. 2,602 genes were differentially expressed between myxomatous and non-myxomatous valves. Canonical TGF-β signaling was increased in MMVD due to increased ligand expression and de-repression of SMAD2/3 signaling and was confirmed with qRT-PCR and immunohistochemistry. Myxomatous valves demonstrated activation of canonical BMP and Wnt/β-catenin signaling and upregulation of their common target Runx2. Our dataset provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-β2 increased β-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-β2 and Wnt signaling. In vivo infusion of mice with angiotensin-II recaptured several changes in signaling pathways characteristic of human MMVD. Conclusion These data support a new disease framework whereby activation of TGF-β2, BMP4, Wnt/β-catenin, or immune signaling play major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease, and open novel avenues guiding future research into the pathogenesis of MMVD.

De novo postoperative LV dysfunction is not uncommon in patients with "normal" preoperative EF undergoing mitral valve repair. LV dysfunction can persist, impairing recovery of LV size, function, and survival. The consideration of mitral repair before the onset of excessive LV dilation or pulmonary hypertension, even in those with preserved EF, seems warranted.

In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy.