Clinical and angiographic outcomes with everolimus eluting stents for the treatment of cardiac allograft vasculopathy.

OBJECTIVES: This study aimed to examine clinical efficacy, safety, and intermediate clinical outcomes with everolimus-eluting stents (EESs) in patients with transplant coronary artery disease (TCAD). BACKGROUND: TCAD is a major cause of mortality in patients following orthotopic heart transplantation (OHT). Systemic everolimus in OHT patients has been shown to reduce TCAD. The safety and efficacy of an EES, the Xience V, have not been evaluated in this population. METHODS: Patients post-OHT with hemodynamically significant CAD who underwent percutaneous coronary intervention (PCI) with EES were included. Participants were maintained on dual antiplatelet therapy for 1-year post-PCI. We examined procedural success, in-hospital and 1-year mortality, stent thrombosis, angiographic restenosis, and myocardial infarction rates. All patients had follow-up angiography 1-year after PCI. Target vessel revascularization (TVR), target lesion revascularization (TLR), in-segment restenosis, target vessel failure (TVF), and lumen late loss were noted. RESULTS: PCI was performed in 34 de novo lesions in 21 patients, and 40 EES were placed. Procedural success rate was 100%. Average stent was 16.5 ± 5.1 mm long and 3.0 ± 0.6 mm in diameter. All patients had angiographic follow-up (409 ± 201 days). There was no stent thrombosis, deaths, or myocardial infarctions during follow-up. Two patients had focal in-stent restenosis. TLR rate was 5.9% (2/34), and TVR rate was 11.1% (3/27). Quantitative coronary angiography (QCA) showed stenosis diameter to be 19.98 ± 17.57%. CONCLUSIONS: Use of an EES is associated with a low incidence of TVR and TLR in patients with TCAD. Further studies are needed to determine whether PCI with EES changes long-term outcomes.

Percutaneous mitral valve repair.

Nonsurgical treatment of clinically important mitral regurgitation (MR) has evolved tremendously over the past decade. Recent studies of percutaneous mitral valve repair procedures have shown that less invasive procedures are safe and can be effective in selected patients. MitraClip has been studied most extensively. The MitraClip is attached to the middle scallop of the mitral leaflets by a transseptal-transvascular approach. The device approximates the leaflets in an edge-to-edge percutaneous repair technique that diminishes MR, improves functional status, and improves left ventricular remodeling. The subgroup that has the most benefit includes patients with older age, poorer left ventricular function, and functional MR and is considered high risk for surgical valve replacement. Other novel percutaneous mitral valve therapies under investigation include indirect and direct annuloplasty, and ventricular remodeling devices.

Development of a selective and scalable N1-indazole alkylation.

N1-Alkyl indazoles are a ubiquitous and privileged motif within medicinal chemistry, yet methods to selectively furnish N1-alkyl indazoles with simple alkyl side chains remain sparse. Herein, negative data from high-throughput experimentation (HTE) enabled a confident pivot of resource from continued optimisation to the development of an alternative reaction. This workflow culminated in a methodology for the synthesis of N1-alkyl indazoles. The procedure is highly selective for N1-alkylation, practical, and broad in scope, with no N2-alkyl products detected at completion. Mechanistic understandings were consistent with attributing the high selectivity to thermodynamic control. Additional data-driven process development led to this reaction being safely demonstrated on a 100 g scale, with potential for further scale up. This study highlights pragmatic principles followed to develop a necessitated methodology, suitable for large scale manufacture.

Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.

Physical activity, hormone replacement therapy, and the presence of coronary calcium in midlife women.

BACKGROUND: Atherosclerotic calcification is a risk factor for cardiovascular events, independent of other traditional risk factors. Studies of the relation of menopausal hormone therapy to cardiovascular events have had inconsistent results, and often have been confounded by lifestyle behaviors and the "healthy user" effect. The authors evaluated the cross-sectional association of hormone therapy use with the presence and severity of atherosclerosis in postmenopausal women, independent of lifestyle factors, including diet and physical activity levels. METHODS: The authors consecutively enrolled postmenopausal asymptomatic women who were referred for coronary artery calcium scanning to measure cardiovascular risk. After consent was obtained, women were interviewed prior to their cardiac scan about cardiac risk factors, hormone therapy use, menopausal status, diet, and physical activity. Coronary artery calcium prevalence was defined as any calcification present (score >0). RESULTS: Of the 544 enrolled women aged 50-80 years, 252 (46.3%) were hormone therapy users. Hormone therapy users had a significantly lower prevalence of any coronary artery calcium (defined as coronary artery calcium score >0; 37%), than non-users (50%, p = 0.04), as well as significantly lower mean calcium scores (p = 0.02). Multiple logistic regression models demonstrated a significantly reduced odds of coronary artery calcium in hormone therapy users compared to non-users with an adjusted odds ratio of 0.58 (p = 0.04), adjusting for traditional cardiac risk factors and body mass index. Women who reported consuming a vegetarian or a high-protein diet had almost two-fold odds of coronary artery calcium compared with women who reported regular, mixed, or low-fat, low-salt diets (OR = 1.78, p = 0.02). Severity of coronary artery calcium was less with increasing levels of physical activity, and a significant association was observed between physical activity and hormone therapy use (adjusted OR = 4.05, p = 0.03), independent of coronary artery calcium severity. CONCLUSION: This cross-sectional study demonstrated a protective association of hormone therapy with the presence and severity of coronary artery calcium. Although a strong relationship was observed between hormone therapy and physical activity, their complex interplay may affect mechanistic biochemical and physiological processes that have yet to be clearly delineated. Thus, physical activity and diet should be taken into account in prospective studies of the relation of hormone therapy use to coronary artery calcium.

Percutaneous approaches to valve repair for mitral regurgitation.

Percutaneous therapy has emerged as an option for treatment of mitral regurgitation for selected, predominantly high-risk patients. Most of the percutaneous approaches are modifications of existing surgical approaches. Catheter-based devices mimic these surgical approaches with less procedural risk, due to their less-invasive nature. Percutaneous annuloplasty can be achieved indirectly via the coronary sinus or directly from retrograde left ventricular access. Catheter-based leaflet repair with the MitraClip (Abbott Laboratories, Abbott Park, Illinois) is accomplished with an implantable clip to mimic the surgical edge-to-edge leaflet repair technique. A large experience with MitraClip has been reported, and several other percutaneous approaches have been successfully used in smaller numbers of patients to demonstrate proof of concept, whereas others have failed and are no longer under development. There is increasing experience in both trials and practice to begin to define the clinical utility of percutaneous leaflet repair, and annuloplasty approaches are undergoing significant development. Transcatheter mitral valve replacement is still in early development.