Genetic variants associated with atrial fibrillation and PR interval following cardiac surgery.

OBJECTIVE: The authors hypothesized that genetic association between atrial fibrillation (AF)-associated and PR-associated genetic loci was biologically mediated through slower conduction velocities for some or all of these loci. DESIGN: Prospectively collected cohort study. SETTING: Single tertiary care university hospital. PARTICIPANTS: A total of 1227 Caucasian patients who underwent coronary artery bypass grafting (CABG). INTERVENTIONS: A total of 677 single nucleotide polymorphisms previously associated with ambulatory AF or PR interval were tested for association with postoperative atrial fibrillation (poAF) and preoperative PR interval, maximum PR interval, maximum change in PR interval, and maximum change in PR interval from preoperative PR interval. MEASUREMENTS AND MAIN RESULTS: The incidence of new-onset poAF was 31%. All of the PR interval variables were longer in the poAF cohort. Two variants on 1q21 and 12 on 4q25 were associated with poAF after adjustment for false discovery rate (FDR), but no variants were associated with PR interval variables after adjustment for FDR. Several variants were associated with both poAF and PR interval variables at p<0.05, but none of them remained significant after adjusting for FDR. CONCLUSION: It was found that patients with poAF have significantly longer PR interval. Genetic variants in both the 1q21 and 4q25 regions associate with poAF after CABG surgery, but the authors were unable to find association between these variants and PR interval after adjusting for FDR

Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury.

Protease-activated receptors (PAR)-1 and -4 are the principal receptors for thrombin-mediated platelet activation. Functional genetic variation has been described in the human PAR1 gene, but not in the PAR4 gene (F2RL3). We sought to identify variants in and around F2RL3 and to determine their association with perioperative myocardial injury (PMI) after coronary artery bypass graft surgery. We further explored possible mechanisms for F2RL3 single nucleotide polymorphism (SNP) associations with PMI including altered receptor expression and platelet activation. Twenty-three SNPs in the F2RL3 gene region were genotyped in two phases in 934 Caucasian subjects. Platelets from 43 subjects (23 major allele, 20 risk allele) homozygous for rs773857 (SNP with the strongest association with PMI) underwent flow cytometry to assess PAR4 receptor number and response to activation by a specific PAR4 activating peptide (AYPGKF) measured by von Willebrand factor (vWf) binding and P-selectin release and PAC-1 binding. We identified a novel association of SNP rs773857 with PMI (OR = 2.4, P = 0.004). rs773857 risk allele homozygotes have significantly increased platelet counts and platelets showed a significant increase in P-selectin release after activation (P = 0.004). We conclude that rs773857 risk allele homozygotes are associated with risk for increased platelet count and hyperactivity

Natriuretic peptide system gene variants are associated with ventricular dysfunction after coronary artery bypass grafting.

BACKGROUND: Ventricular dysfunction (VnD) after primary coronary artery bypass grafting is associated with increased hospital stay and mortality. Natriuretic peptides have compensatory vasodilatory, natriuretic, and paracrine influences on myocardial failure and ischemia. The authors hypothesized that natriuretic peptide system gene variants independently predict risk of VnD after primary coronary artery bypass grafting. METHODS: A total of 1,164 patients undergoing primary coronary artery bypass grafting with cardiopulmonary bypass at two institutions were prospectively enrolled. After prospectively defined exclusions, 697 patients of European descent (76 with VnD) were analyzed. VnD was defined as need for at least 2 new inotropes and/or new mechanical ventricular support after coronary artery bypass grafting. A total of 139 haplotype-tagging single nucleotide polymorphisms (SNPs) within 7 genes (NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, CORIN) were genotyped. SNPs univariately associated with VnD were entered into logistic regression models adjusting for clinical covariates predictive of VnD. To control for multiple comparisons, permutation analyses were conducted for all SNP associations. RESULTS: After adjusting for clinical covariates and multiple comparisons within each gene, seven NPPA/NPPB SNPs (rs632793, rs6668352, rs549596, rs198388, rs198389, rs6676300, rs1009592) were associated with decreased risk of postoperative VnD (additive model; odds ratios 0.44-0.55; P = 0.010- 0.036) and four NPR3 SNPs (rs700923, rs16890196, rs765199, rs700926) were associated with increased risk of postoperative VnD (recessive model; odds ratios 3.89-4.28; P = 0.007-0.034). CONCLUSIONS: Genetic variation within the NPPA/NPPB and NPR3 genes is associated with risk of VnD after primary coronary artery bypass grafting. Knowledge of such genotypic predictors may result in better understanding of the molecular mechanisms underlying postoperative VnD

A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: Insights from the international BAVCon (bicuspid aortic valve consortium)

Bicuspid aortic valve (BAV) is the most common adult congenital heart defect and is found in 0.5% to 2.0% of the general population. The term "BAV" refers to a heterogeneous group of disorders characterized by diverse aortic valve malformations with associated aortopathy, congenital heart defects, and genetic syndromes. Even after decades of investigation, the genetic determinants of BAV and its complications remain largely undefined. Just as BAV phenotypes are highly variable, the genetic etiologies of BAV are equally diverse and vary from complex inheritance in families to sporadic cases without any evidence of inheritance. In this paper, the authors discuss current concepts in BAV genetics and propose a roadmap for unraveling unanswered questions about BAV through the integrated analysis of genetic and clinical data. © 2014 by the American College of Cardiology Foundation

Variation in the 4q25 chromosomal locus predicts atrial fibrillation after coronary artery bypass graft surgery.

Atrial fibrillation (AF) is the most common adverse event following coronary artery bypass graft surgery. A recent study identified chromosome 4q25 variants associated with AF in ambulatory populations. However, their role in postoperative AF is unknown. We hypothesized that genetic variants in the 4q25 chromosomal region are independently associated with postoperative AF after coronary artery bypass graft surgery. METHODS AND RESULTS: Two prospectively collected cohorts of patients undergoing coronary artery bypass graft surgery, with or without concurrent valve surgery, at 3 US centers. From a discovery cohort of 959 patients, clinical and genomic multivariate predictors of postoperative AF were identified by genotyping 45 single-nucleotide polymorphisms (SNPs) encompassing the 4q25 locus. Three SNPs were then assessed in a separately collected validation cohort of 494 patients. After adjustment for clinical predictors of postoperative AF and multiple comparisons, rs2200733, rs13143308, and 5 other linked SNPs independently predicted postoperative AF in the discovery cohort. Additive odds ratios for the 7 associated 4q25 SNPs ranged between 1.57 and 2.17 (P=8.0x10(-4) to 3.4x10(-6)). Association with postoperative AF were measured and replicated for rs2200733 and rs13143308 in the validation cohort. CONCLUSIONS: In 2 independently collected cardiac surgery cohorts, noncoding SNPs within the chromosome 4q25 region are independently associated with postoperative AF after coronary artery bypass graft surgery after adjusting for clinical covariates and multiple comparisons

Mode de vie et cancer du sein: quels conseils pour la prise en charge de l’après cancer ?

National audienceIt is widely admitted that after adjuvant therapy, about one half of women with localized breast cancer experience a weight gain of 3 kg. It can however reach 8 to 10 kg in numerous cases. Risk factors associated with weight gain are unclear, but women undergoing chemotherapy seem to have an increased risk, especially before the menopause. Retrospective studies suggest that post-treatment weight gain mightincrease the risk of relapse. Furthermore, the only intervention trial in adjuvant breast cancer, though impaired by methodological pitfalls, suggests that limiting weight gain could increase disease free survival. The use of nutritional complements by cancer patients is usually underestimated. Several compounds, such as vitamins C and, E, selenium or carotenoids, have been investigated in clinical trials whose quality is usually poor. Available date nevertheless suggest a deleterious effect of supplementation with anti-oxydants, in particular at supraphysiological doses. The WHEL trial is the only large randomised trial investigating an healthy diet with vegetables, fruits and fiber after localized breast cancer. An effect of survival is observed in the experimental arm only in patients with sufficient level of physical activity. Physical activity, when practiced regularly, improves asthenia, quality of life and even survival, without any detrimental effect. It should however be initiated after an evaluation of patient’s ability and comorbidities, and be realized in specific centers with careful medical follow-up. Its mechanisms of action include regulation of estrogen, insulin, IGF1 and adipokines. Adapted physical activity should be proposed to patients fulfilling precise inclusion criteria.On estime que près de la moitié des femmes traitées pour un cancer du sein localisé sont affectées par un gain de l’ordre de 3 kg, mais des prises de poids de l’ordre de 8 à 10 kg ne sont pas exceptionnelles. Les facteurs de risque ne sont pas clairement individualisés, mais les patientes recevant une chimiothérapie semblent plus concernées, en particulier avant la ménopause. Les études rétrospectives montrent que la prise de poids pourrait être un facteur de risque de rechute, qui plus est, le seules said’ intervention actuellement publié dans le cancer du sein, bien que sujet à des critiques d’ordre méthodologique, suggère un effet positif de la réduction du surpoids sur la survie sans récidive. L’utilisation de compléments nutritionnels par les patients est, quant à elle, largement sous-estimée. De nombreux composés ont fait l’objet d’essais cliniques dont la méthodologie est globalement peu convaincante (vitamines C et E, sélénium, caroténoïdes). Les données disponibles suggèrent un effet négatif de la supplémentation en antioxydants(en particulier à des doses supra-physiologiques) pouvant éventuellement affecter l’efficacité du traitement antitumoral. L’essai WHEL (Women’s Healthy Eating and Living) est le seul grand essai randomisé d’intervention, basé sur une supplémentation en fruits et légumes après traitement d’un cancer du sein localisé : il suggère un effet positif de la supplémentation uniquement si elle est associée à une activité physique suffisante. L’ activité physique régulière lors des soins en cancérologie améliore la qualité de vie, la fatigue, la survie, enparticulier pour les patientes por-teuses de cancer du sein, et ce, sans effet secondaire à condition d’être mise en place après un bilan précis des capacités, des comorbidités, d’être réalisée dans des structures adaptées avec un suivi médical des progrès et des difficultés. Les mécanismes d’action passent par des modifications de sécrétion d’estrogène, d’insuline, d’IGF1 et des adipokines. L’activité physique adaptée en cancérologie doit être proposée aux malades répondant à des critères d’inclusion précis