Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown. OBJECTIVE: The purpose of this study was to investigate the prevalence of somatic variants in AF candidate genes in an AF patient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF. METHODS: DNA was extracted from blood and left atrial tissue from 44 AF patients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques. RESULTS: No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1 candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2). CONCLUSION: We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AF patients might, like lone AF patients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.

Brugada syndrome risk loci seem protective against atrial fibrillation.

Several studies have shown an overlap between genes involved in the pathophysiological mechanisms of atrial fibrillation (AF) and Brugada Syndrome (BrS). We investigated whether three single-nucleotide polymorphisms (SNPs) (rs11708996; G>C located intronic to SCN5A, rs10428132; T>G located in SCN10A, and rs9388451; T>C located downstream to HEY2) at loci associated with BrS in a recent genome-wide association study (GWAS) also were associated with AF. A total of 657 patients diagnosed with AF and a control group comprising 741 individuals free of AF were included. The three SNPs were genotyped using TaqMan assays. The frequencies of risk alleles in the AF population and the control population were compared in two-by-two models. One variant, rs10428132 at SCN10A, was associated with a statistically significant decreased risk of AF (odds ratio (OR)=0.77, P=0.001). A meta-analysis was performed by enriching the control population with allele frequencies from controls in the recently published BrS GWAS (2230 alleles). In this meta-analysis, both rs10428132 at SCN10A (OR=0.73, P=5.7 × 10(-6)) and rs11708996 at SCN5A (OR=0.80, P=0.02) showed a statistically significant decreased risk of AF. When assessing the additive effect of the three loci, we found that the risk of AF decreased in a dose-responsive manner with increasing numbers of risk alleles (OR=0.50, P=0.001 for individuals carrying ≥4 risk alleles vs ≤1 allele). In conclusion, the prevalence of three risk alleles previously associated with BrS was lower in AF patients than in patients free of AF, suggesting a protective role of these loci in developing AF.

Chest pain after coronary artery bypass: relation to coping capacity and quality of life.

OBJECTIVE: To investigate relations between chest pain after coronary artery bypass grafting (CABG), quality of life (QoL), and coping capacity. DESIGN: Two groups were included, Group I (n = 111) was evaluated before and 1 year postoperatively, and Group II (n = 102) once, at 3 years. The questionnaire included parts of the Seattle angina questionnaire, one question concerning chest pain, coping capacity (sense of coherence), emotional state, the Psychological general well-being index, and a global QoL question. RESULTS: Chest pain was significantly related to lower coping capacity (at 1 year) and lower QoL scores (at 1 and 3 years). Changes of coping capacity and emotional state from before to 1 year after the CABG did not reach statistical significance in the chest pain group while the no chest pain patients had significantly better emotional state. The relation between chest pain and worse QoL was significantly reduced by high coping capacity. CONCLUSION: Independent of the direction of causality, the patient's coping capacity and experienced chest pain is highly related.

Use of biochemical markers of infarction for diagnosing perioperative myocardial infarction and early graft occlusion after coronary artery bypass surgery.

STUDY OBJECTIVES: Perioperative myocardial infarction (PMI) during coronary artery bypass grafting (CABG) is an important clinical problem because it is closely associated with increased morbidity and mortality. The diagnosis of PMI is, however, associated with several problems. Due to the surgical trauma, the usual indicators of myocardial infarction (pain, ECG changes, and elevated biochemical markers of infarction) have uncertain diagnostic value. The primary aim of this study was to illustrate the levels of the biochemical markers after uncomplicated bypass surgery defined as no clinical or ECG evidence of PMI, and no graft occlusion at 7 days by repeat angiography; and secondarily, to establish biochemical diagnostic discrimination limits for detection of in-hospital graft occlusion. METHODS AND RESULTS: One hundred three patients undergoing elective CABG were closely monitored by serial measurements of creatine kinase (CK)-MB mass, myoglobin, troponin T, and troponin I, and underwent a repeat angiography before discharge. Seven patients had ECG evidence of PMI. Peak troponin T and CK-MB values were significantly higher in these seven patients, although the diagnostic performances of the optimally chosen cutoff levels for diagnosing AMI were fair. Twelve patients had at least one occluded graft shown by repeat angiography. Peak values of CK-MB and troponin T were significantly higher in patients with graft occlusion (52.2 microg/L vs 24.7 microg/L, p = 0.01; and 3.7 microg/L vs 1.0 microg/L, p = 0.05, respectively). By multivariate analysis, a diagnostic discrimination level of 30 microg/L for CK-MB did not reach statistical significance; however, the independent diagnostic value of a cutoff level for troponin T at 3 microg/L reached a level of significance (p = 0.06). DISCUSSION: We have suggested normal values of four different biochemical markers of infarction after uncomplicated coronary bypass surgery. Patients with in-hospital graft occlusion had higher peak CK-MB and troponin T values. However, the overlap with patients without graft occlusion is substantial, and the patency status in the individual cannot be reliably predicted from these noninvasive tests.