Purpose of review Metabolic syndrome (MetS) is a cluster of inter-related and heritable metabolic traits, which collectively impart unsurpassed risk for atherosclerotic cardiovascular disease and type 2 diabetes. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Recent findings Genome-wide association studies (GWAS) have been widely utilized albeit with modest success in identifying variants that are associated with more than two metabolic traits. Another limitation of this approach is the inherent small effect of the common variants, a major barrier for dissecting their cognate pathways. Modest advances in this venue have been also made by genetic studies of kindreds at the extreme ends of quantitative distributions. These efforts have led to the discovery of a number of disease genes with large effects that underlie the association of diverse traits of this syndrome. Summary Substantial progress has been made over the last decade in identification of genetic risk factors associated with the various traits of MetS. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits. Genetic investigations of outlier kindreds or homogenous populations with high prevalence for the disease can potentially improve our knowledge of the disease pathophysiology.

Background With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The utility of whole exome sequencing (WES) for clinical diagnosis, risk stratification and management of inherited CVD has not been previously evaluated. Methods and Results We analyzed the results of WES in first two hundred adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (p=0.04). WES was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death (SCD), in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to discovery of novel candidate genes in another 14% of the cases. Conclusions WES is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited cardiovascular diseases, particularly for poorly defined cases of SCD. By presenting novel candidate genes and their potential disease associations we also provide evidence for the utility of this genetic tool for identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown cardiovascular disease genes.

Objective This study assessed whether a structured nurseled diabetes educational program underpinned by the theories of the health belief model, change in locus of control, and patient empowerment is effective in improving glycemic and metabolic parameters among South Asians with type II diabetes compared to regular outpatient care. Methods This was a parallel-group randomized trial in South Asian adult patients with type II diabetes living in Qatar. 460 subjects were randomized to a nurse-led, groupbased diabetes educational program (n = 230) or to usual care (n = 230). The primary outcome was the improvement in HbA1c and other metabolic parameters, including lipid profile, albumin/creatinine ratio, blood pressure, and body mass index. Patients in the intervention group were invited to attend four 2-h sessions of self-efficacy improvement education once weekly. Outcomes were assessed at baseline and 12 months later. An intention-totreat analysis was performed using repeated measures ANOVA (analysis of variance) for each of the clinical outcome variables. Results After 12 months, 290 patients completed the study. Subjects in the intervention group had statistically significant improvements in HbA1c (-0.55 %, p = 0.012), fasting blood sugar (-16.6 mg/dl, p = 0.022), albumin/ creatinine ratio (-3.09, p \ 0.001), and HDL cholesterol (?6.08 mg/dl, p \ 0.0001). Conclusion The inclusion of South Asian patients with type II diabetes in a structured, theory-based diabetes educational program that is led by nurses improves glycemic and metabolic parameters after 12 months.

Metabolic syndrome is a cluster of inherited metabolic traits, which centers around obesity and insulin resistance and is a major contributor to the growing prevalence of cardiovascular disease. The factors that underlie the association of metabolic traits in this syndrome are poorly understood due to disease heterogeneity and complexity. Genetic studies of kindreds with severe manifestation of metabolic syndrome have led to the identification of casual rare mutations in the LDL receptor-related protein 6, which serves as a co-receptor with frizzled protein receptors for Wnt signaling ligands. Extensive investigations have since unraveled the significance of the Wnt pathways in regulating body mass, glucose metabolism, de novo lipogenesis, low-density lipoprotein clearance, vascular smooth muscle plasticity, liver fat, and liver inflammation. The impaired canonical Wnt signaling observed in the R611C mutation carriers and the ensuing activation of noncanonical Wnt signaling constitute the underlying mechanism for these cardiometabolic abnormalities. Transcription factor 7-like 2 is a key transcription factor activated through LDL receptor-related protein 6 canonical Wnt and reciprocally inhibited by the noncanonical pathway. TC7L2 increases insulin receptor expression, decreases low-density lipoprotein and triglyceride synthesis, and inhibits vascular smooth muscle proliferation. Canonical Wnt also inhibits noncanonical protein kinase C, Ras homolog gene family member A, and Rho associated coiled-coil containing protein kinase 2 activation, thus inhibiting steatohepatitis and transforming growth factor β-mediated extracellular matrix deposition and hepatic fibrosis. Therefore, dysregulation of the highly conserved Wnt signaling pathway underlies the pleiotropy of metabolic traits of the metabolic syndrome and the subsequent end-organ complications.

Pulmonary embolism (PE) is a common, potentially fatal thrombotic disease. Atrial fibrillation (AF), the most common arrhythmia, may also lead to thromboembolic complications. Although initially appearing as distinct entities, PE and AF may coexist. The direction and extent of this association has not been well characterized. We performed a search of PubMed, Scopus, and the Cochrane Database of Systematic Reviews for publications that reported coexisting AF in patients with PE, or vice versa, to provide a systematic overview of pathophysiological and epidemiological aspects of this association (last search: October 13, 2016). We screened 650 articles following the PubMed search, and 697 through Scopus. PE and AF share many common risk factors, including old age, obesity, heart failure, and inflammatory states. In addition, PE may lead to AF through right-sided pressure overload or inflammatory cytokines. AF, in turn, might lead to right atrial appendage clot formation and thereby PE. Epidemiological studies indicate that AF can be seen as a presenting sign, during the early phase, or later in the course of recovery from PE. Patients with AF are also at increased risk of developing PE, a risk that correlates with the CHADS-VASc score. For the choice of antithrombotic therapy, PE-related factors (provoked or unproved, active cancer, and prior recurrence) and AF-related factors (CHADS-VASc score), risk of bleeding, and patient preferences should be considered. In conclusion, PE and AF may coexist, with an understudied bidirectional association. Prognostication and choice of antithrombotic therapy in patients with both PE and AF might be different compared with those who present with only one of the two and warrants further investigation.