Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Neutrophil-to-Lymphocyte Ratio Associated With Adverse Events After Endovascular Aneurysm Repair (EVAR).

BACKGROUND: The blood neutrophil-to-lymphocyte ratio (NLR) is a surrogate biomarker of systemic inflammation with important prognostic significance in multiple disease processes, including cardiovascular diseases. It is inexpensive, widely available, and may be related to the outcomes of patients after surgery. We aimed to investigate the possible association of NLR with the outcomes of patients following endovascular aneurysm repair (EVAR). METHODS: This single-center, retrospective study of a prospectively maintained database evaluated 777 patients with a diagnosed abdominal aortic aneurysm (AAA) who underwent EVAR and were longitudinally followed between 2001 and 2017. NLR was defined as the ratio of absolute neutrophil count to absolute lymphocyte count. The mortality and reinterventions were used to evaluate outcomes using the appropriate univariate models, and the effect of clinical variables on NLR was further investigated using multivariate modelling. RESULTS: The median NLR for all patients was 3 IQR [2.2 - 4.6]. A cut-off point of 3.6 was uncovered in a training set of 388 patients using the maximally ranked statistic method. Patients with NLR < 3.6 had significantly improved mortality rates (P< 0.0001) in the training set, and results were internally validated in a testing set of 389 patients (P = 0.042). Multivariate analysis revealed that high NLR (HR 1.4 95% CI [1.0 - 2.0]; P< 0.05) remained an independent predictor of mortality in a multivariate analysis controlling for characteristics such as comorbidities, age, and maximal aortic diameter. 5-year mortality and 30-day, 1-year and 5-year reinterventions were all higher in the high NLR group. CONCLUSION: High NLR was significantly associated with higher rates of death at 5 years as well as higher rates of reinterventions at 30 days, 1 year and 5 years. We also suggest that an internally validated cut-off point of NLR >3.6 may be clinically important to help segregate patients into high and low NLR categories. It remains unclear whether NLR is directly linked to adverse events post-EVAR or whether it is a surrogate for an inflammatory state that predisposes patients to higher risk of death or reinterventions.

The Role of Bone Morphogenetic Protein Signaling in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.

Transcatheter Tricuspid and Pulmonary Valve Repair and Replacement.

Severe tricuspid regurgitation (TR) is associated with significant mortality and morbidities. Currently, surgical tricuspid repair with annuloplasty is the gold standard treatment. However, the prohibitive risks of open surgery and increasing evidence that severe TR should be intervened on early has led to an outburst in the development and evolution of transcatheter tricuspid valve interventions (TTVI). These technologies are broadly categorized into direct suture annuloplasty devices, minimally invasive annuloplasty, direct ring annuloplasty devices, coaptation-based strategies, edge-to-edge repair devices, and transcatheter valve replacement. Each has its own set of advantages and limitations and have been tried, to varying degrees of success, in a myriad of pathoanatomic scenarios. Challenges faced in TTVI device and trial designs include heterogeneous patient populations, the need for quality imaging, variations of imaging requirements and anatomic criteria by device, hard-to-define clinical endpoints, and the poor prognosis carried by significant residual TR. Similar to tricuspid valve disease, pulmonic valve (PV) disease can occur on its own or secondary to a congenital heart defect, most commonly tetralogy of Fallot. Many patients with pulmonic stenosis or insufficiency often require repeat surgical interventions for other cardiac problems, highlighting the importance of developing transcatheter approaches to reduce the number of repeat open-heart surgeries required. Transcatheter PV replacement (TPVR) is growing in use and is the procedure of choice in patients with failed bioprostheses via valve-in-valve implantation. The Melody (Medtronic Inc., Minneapolis, Minnesota) and SAPIEN XT (Edwards Lifesciences Inc., Irvine, California) devices are the currently available TPVR technologies. Current limitations here include device kinking, the risk of stent fracture, anatomic difficulties, such as asymmetric right ventricular outflow tracts leading to poor landing zones and procedural risks of coronary artery and aortic root compression.

The Use of Transcatheter Devices for Mitral Repair and Replacement.

Recent advances in device design have resulted in a wide variety of transcatheter treatment options for patients with symptomatic mitral valve disease. Surgery remains the gold standard for patients with symptomatic, primary mitral regurgitation, while transcatheter devices can be considered in higher-risk patients. For secondary mitral regurgitation, optimal medical therapy and cardiac resynchronization are recommended. Recent evidence suggests that transcatheter alternatives may be considered as well. This review will provide an overview of current transcatheter mitral repair and replacement technologies. These include those that mimic open surgical procedures such as edge-to-edge repair, choral replacement, direct annuloplasty, and valve replacement.

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

Optimal Treatment of Uncomplicated Type B Aortic Dissection: JACC Review Topic of the Week.

Historically, the gold standard for treating acute uncomplicated type B aortic dissection (TBAD) has been aggressive medical therapy to achieve optimal heart rate and blood pressure control. However, recent data have demonstrated that a significant proportion of patients with medically managed acute uncomplicated TBAD have late aorta-related complications, such as aneurysmal degeneration, that increase mortality and often necessitate surgical intervention. In this review, the authors review existing literature on uncomplicated TBAD and highlight contemporary surgical and medical strategies to manage this condition. Looking ahead, efforts are underway to identify and characterize a high-risk subgroup of acute uncomplicated TBAD patients who may benefit from early intervention.

Hepcidin Deficiency Protects Against Atherosclerosis.

Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.