Polymorphism rs7214723 in CAMKK1: a new genetic variant associated with cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. CVDs have a complex etiology due to the several factors underlying its development including environment, lifestyle, and genetics. Given the role of calcium signal transduction in several CVDs, we investigated via PCR-restriction fragment length polymorphism (RFLP) the single nucleotide polymorphism (SNP) rs7214723 within the calcium/calmodulin-dependent kinase kinase 1 (CAMKK1) gene coding for the Ca2+/calmodulin-dependent protein kinase kinase I. The variant rs7214723 causes E375G substitution within the kinase domain of CAMKK1. A cross-sectional study was conducted on 300 cardiac patients. RFLP-PCR technique was applied, and statistical analysis was performed to evaluate genotypic and allelic frequencies and to identify an association between SNP and risk of developing specific CVD. Genotype and allele frequencies for rs7214723 were statistically different between cardiopathic and several European reference populations. A logistic regression analysis adjusted for gender, age, diabetes, hypertension, BMI and previous history of malignancy was applied on cardiopathic genotypic data and no association was found between rs7214723 polymorphism and risk of developing specific coronary artery disease (CAD) and aortic stenosis (AS). These results suggest the potential role of rs7214723 in CVD susceptibility as a possible genetic biomarker

Long-Term Survival in Patients with Post-Operative Atrial Fibrillation after Cardiac Surgery: Analysis from a Prospective Cohort Study

9noopenBackground: Post-operative (POP) atrial fibrillation (AF) is frequent in patients who undergo cardiac surgery. However, its prognostic impact in the long term remains unclear. Methods: We followed 1386 patients who underwent cardiac surgery for an average of 10 ± 3 years. According to clinical history of AF before and after surgery, four subgroups were identified: (1) patients with no history of AF and without episodes of AF during the first 30 days after surgery (control or Group 1, n = 726), (2) patients with no history of AF before surgery in whom new-onset POP AF was detected during the first 30 days after surgery (new-onset POP AF or Group 2, n = 452), (3) patients with a history of paroxysmal/persistent AF before cardiac surgery (Group 3, n = 125, including 87 POP AF patients and 38 who did not develop POP AF), and (4) patients with permanent AF at the time of cardiac surgery (Group 4, n = 83). All-cause mortality was the primary outcome of the study. We tested the associations of potential determinants with all-cause mortality using univariable and multivariable statistical analyses. Results: Overall, 473 patients (34%) died during follow-up. After adjustment for multiple confounders, new-onset POP AF (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 0.90-1.89; p = 0.1609), history of paroxysmal/persistent AF before cardiac surgery (HR = 1.33, 95% CI: 0.71-2.49; p = 0.3736), and permanent AF (Group 4) (HR = 1.55, 95% CI 0.82-2.95; p = 0.1803) were not associated with a significantly increased risk of mortality when compared with Group 1 (patients with no history of AF and without episodes of AF during the first 30 days after surgery). In new-onset POP AF patients, oral anticoagulation was not associated with mortality (HR = 1.13, 95% CI: 0.83-1.54; p = 0.4299). Conclusions: In this cohort of patients who underwent different types of heart surgery, POP AF was not associated with an increased risk of mortality. In this setting, the role of long-term anticoagulation remains unclear.openMarazzato, Jacopo; Masnaghetti, Sergio; De Ponti, Roberto; Verdecchia, Paolo; Blasi, Federico; Ferrarese, Sandro; Trapasso, Monica; Spanevello, Antonio; Angeli, FabioMarazzato, Jacopo; Masnaghetti, Sergio; De Ponti, Roberto; Verdecchia, Paolo; Blasi, Federico; Ferrarese, Sandro; Trapasso, Monica; Spanevello, Antonio; Angeli, Fabi

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma.

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme

Fluctuations in warfarin dose response after heart valve surgery: implications for cardiac rehabilitation

In patients undergoing heart valve surgery (HVS) who require warfarin therapy, the maintenance of low variability in the level of anticoagulation early after operation is generally difficult. Aim of this study was to evaluate the time in therapeutic range (TTR) in HVS patients receiving oral anticoagulation therapy (OAT) during phase I-II of cardiac rehabilitation (CR), and, secondly, to identify clinical variables associated with inadequate anticoagulation. Methods: Observational study of consecutive in-hospital patients directly tracked from a cardiac surgery unit to a CR facility. OAT was monitored both in terms of administered warfarin doses and resulted INR values, from day 1 to day 15 after operation. Clinical variables were tested in a logistic regression model for the prediction of inadequate anticoagulation, defined as the presence of nontherapeutic INRs for ≥5 days between day 8 and 15. Results: Eighty-one patients (males 56%, age 62±19 yrs.), following valvuloplasty (37%), mechanical (17%), and bioprosthetic (45%) valve replacement were considered. The prescribed warfarin dosages were significantly higher from day 1 to day 7 than from day 8 to day 15 (4.6±3.6 and 3.0±1.1 mg respectively, p< 0.001). Overall, TTR was 6±3 days, while time with elevated and lower INRs accounted for 1.3±1.6 and 8.0±3.5 days respectively. At day 7, only 25% of patients (n= 20) showed a therapeutic INR value. Inadequate anticoagulation between postoperative day 8 and 15 was displayed in 41 (51%) patients, with hypertension as the only independent predictor (p< 0.001) at multivariate analysis. Conclusions: Despite intensive monitoring, half of patients have nontherapeutic INR values (mainly subtherapeutic) in the first two weeks after HVS while on warfarin. Giving the high risk of completing the hospitalization phase without a stable OAT in many patients, both cardiac surgeons and cardiologists should not miss the opportunity to improve patients education, and consider a direct track to anticoagulation management services after discharge

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Transthoracic echocardiography is adequate for the diagnosis of right coronary artery aneurysms

Coronary artery aneurysms (CAA) are rare but potentially fatal pathologies. This case was referred to our Unit after occasional echocardiographic finding of an intracardiac mass. A new detailed transthoracic echocardiogram was decisive for a diagnosis of a large CAA of the right coronary artery, compressing and dislocating the right atrium. Transesophageal echocardiography was not performed because of the data obtained. The diagnosis was confirmed by cardiac catheterization. The patient was managed with a surgical procedure

Coronary artery aneurysm: management and association with abdominal aortic aneurysm

Coronary artery aneurysm (CAA) is a dilatation that exceeds 1.5 times the diameter of a normal adjacent coronary artery. Several studies suggest that pathogenetic mechanisms involved in this disease and in abdominal aortic aneurysm (AAA) are similar. Surgery for CAA is mandatory when the aneurysm is three to four times larger than the original vessel diameter. We reviewed our experience in the surgical treatment of this unusual disease and analyzed its association with AAA