Evaluation of a Prediction Model for the Development of Atrial Fibrillation in a Repository of Electronic Medical Records.

IMPORTANCE: Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and health care expenditures. Accurate prediction of incident AF would enhance AF management and potentially improve patient outcomes. OBJECTIVE: To validate the AF risk prediction model originally developed by the Cohorts for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation (CHARGE-AF) investigators using a large repository of electronic medical records (EMRs). DESIGN, SETTING, AND PARTICIPANTS: In this prediction model study, deidentified EMRs of 33 494 individuals 40 years or older who were white or African American and had no history of AF were reviewed and analyzed. The participants were followed up in the internal medicine outpatient clinics at Vanderbilt University Medical Center for incident AF from December 31, 2005, until December 31, 2010. Adjusting for differences in baseline hazard, the CHARGE-AF Cox proportional hazards model regression coefficients were applied to the EMR cohort. A simple version of the model with no echocardiographic variables was also evaluated. Data were analyzed from October 31, 2013, to January 31, 2014. MAIN OUTCOMES AND MEASURES: Incident AF. Predictors in the model included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, type 2 diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. RESULTS: Among the 33 494 participants, the median age was 57 (interquartile range, 49-67) years; 57% of patients were women, 43% were men, 85.7% were white, and 14.3% were African American. During the mean (SD) follow-up of 4.8 (0.9) years, 2455 individuals (7.3%) developed AF. Both models had poor calibration in the EMR cohort, with underprediction of AF among low-risk individuals and overprediction of AF among high-risk individuals (10th and 90th percentiles for predicted probability of incident AF, 0.005 and 0.179, respectively). The full CHARGE-AF model had a C index of 0.708 (95% CI, 0.699-0.718) in our cohort. The simple model had similar discrimination (C index, 0.709; 95% CI, 0.699-0.718; P = .70 for difference between models). CONCLUSIONS AND RELEVANCE: Despite reasonable discrimination, the CHARGE-AF models showed poor calibration in this EMR cohort. This study highlights the difficulties of applying a risk model derived from prospective cohort studies to an EMR cohort and suggests that these AF risk prediction models be used with caution in the EMR setting. Future risk models may need to be developed and validated within EMR cohorts.

Measurement of diffuse ventricular fibrosis with myocardial T1 in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI. METHODS: Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1. RESULTS: One hundred fifty-seven patients were studied (32% women; median age, 61 years [interquartile range {IQR}, 55-67], 50% persistent AF [episodes>7 days or requiring electrical or pharmacologic cardioversion], 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381-428). AF at the time of CMRI was associated with a 4.4% shorter T1 (p=0.000) compared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate<60). A post-hoc multivariate model adjusted for heart rate suggested that heart rate elevation (p=0.009) contributes to the reduction in T1 observed in patients with AF at the time of CMRI. No association between ventricular T1 and AF recurrence after ablation was demonstrated. CONCLUSION: AF at the time of CMRI was associated with lower post-contrast ventricular T1 compared with sinus rhythm. This effect was at least partly due to elevated heart rate. T1 was not associated with the recurrence of AF after ablation.

Genetic and clinical risk prediction model for postoperative atrial fibrillation.

BACKGROUND: Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model. METHODS AND RESULTS: We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001). CONCLUSIONS: We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies.

A common variant on chromosome 4q25 is associated with prolonged PR interval in subjects with and without atrial fibrillation.

Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25-tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n = 169) and typical (n = 269) AF enrolled in the Vanderbilt AF registry and controls (n = 1,403) derived from the Vanderbilt DNA Biobank were studied. Carriage of the rs2200733T allele (CT or TT genotype) was more common in patients with lone (39%) than typical (25%) AF or controls (21%, p <0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms, respectively, for lone, p = 0.038 and 166, 180, and 196 ms, respectively, for typical, p = 0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size of 10.9, 12.8, and 4.4 ms for patients with lone and typical AF and controls, respectively (p <0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF.

Candidate gene approach to identifying rare genetic variants associated with lone atrial fibrillation.

BACKGROUND: Rare variants in candidate atrial fibrillation (AF) genes have been associated with AF in small kindreds. The extent to which such polymorphisms contribute to AF is unknown. OBJECTIVE: The purpose of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a large cohort of unrelated lone AF probands. METHODS: We resequenced 45 candidate genes in 303 European American (EA) lone AF probands (186 lone AF probands screened for each gene on average [range 89-303], 63 screened for all) identified in the Vanderbilt AF Registry (2002-2012). Variants detected were screened against 4300 EAs from the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency ≤0.04%) AAC variants and these were tested for AF co-segregation in affected family members where possible. RESULTS: Median age at AF onset was 46.0 years [interquartile range 33.0-54.0], and 35.6% had a family history of AF. Overall, 63 very rare AAC variants were identified in 60 of 303 lone AF probands, and 10 of 19 (52.6%) had evidence of co-segregation with AF. Among the 63 lone AF probands who had 45 genes screened, the very rare variant burden was 22%. Compared with the 4300 EA ESP, the proportion of lone AF probands with a very rare AAC variant in CASQ2 and NKX2-5 was increased 3-5-fold (P <.05). CONCLUSION: No very rare AAC variants were identified in ~80% of lone AF probands. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors.

Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion.

BACKGROUND: Genome-wide association studies have identified numerous common polymorphisms associated with atrial fibrillation (AF). The 3 loci most strongly associated with AF occur at chromosome 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3). OBJECTIVE: To evaluate whether timing of AF recurrence after direct current cardioversion (DCCV) is modulated by common AF susceptibility alleles. METHODS: A total of 208 patients (age 65 ± 11 years; 77% men) with persistent AF underwent successful DCCV and were prospectively evaluated at 3, 6, and 12 months for AF recurrence. Four single nucleotide polymorphisms--rs2200733 and rs10033464 at 4q25, rs7193343 in ZFHX3, and rs13376333 in KCNN3--were genotyped. RESULTS: The final study cohort consisted of 184 patients. In 162 (88%) patients, sinus rhythm was restored with DCCV, of which 108 (67%) had AF recurrence at a median of 60 (interquartile range 29-176) days. In multivariable analysis, the presence of any common single nucleotide polymorphism (rs2200733, rs10033464) at the 4q25 locus was an independent predictor of AF recurrence (hazard ratio 2.1; 95% confidence interval 1.21-3.30; P = .008). Furthermore, rs2200733 exhibited a graded allelic dose response for early AF recurrence (homozygous variants: 7 [interquartile range 4-56] days; heterozygous variants: 54 [28-135] days; and wild type: 64 [29-180] days; P = .03). CONCLUSIONS: To our knowledge, this is the first study to evaluate whether genomic markers can predict timing of AF recurrence in patients undergoing elective DCCV. Our findings show that a common polymorphism on chromosome 4q25 (rs2200733) is an independent predictor of AF recurrence after DCCV and point to a potential role of stratification by genotype.

Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation.

BACKGROUND: Common single nucleotide polymorphisms at chromosome 4q25 (rs2200733, rs10033464) are associated with both lone and typical atrial fibrillation (AF). Risk alleles at 4q25 have recently been shown to predict recurrence of AF after ablation in a population of predominately lone AF, but lone AF represents only 5%-30% of AF cases. OBJECTIVE: To test the hypothesis that 4q25 AF risk alleles can predict response to AF ablation in the majority of AF cases. METHODS: Patients enrolled in the Vanderbilt AF Registry underwent 378 catheter-based AF ablations (median age 60 years; 71% men; 89% typical AF) between 2004 and 2011. The primary end point was time to recurrence of any nonsinus atrial tachyarrhythmia (atrial tachycardia, atrial flutter, or AF). RESULTS: Two-hundred atrial tachycardia, atrial flutter, or AF recurrences (53%) were observed. In multivariable analysis, the rs2200733 risk allele predicted a 24% shorter recurrence-free time (survival time ratio 0.76; 95% confidence interval [CI] 0.6-0.95; P = .016) compared with wild type. The heterozygous haplotype demonstrated a 21% shorter recurrence-free time (survival time ratio 0.79; 95% CI 0.62-0.99) and the homozygous risk allele carriers a 39% shorter recurrence-free time (survival time ratio 0.61; 95% CI 0.37-1.0; P = .037). CONCLUSIONS: Risk alleles at the 4q25 loci predict impaired clinical response to AF ablation in a population of patients with predominately typical AF. Our findings suggest that the rs2200733 polymorphism may hold promise as an objectively measured patient characteristic that can be used as a clinical tool for selecting patients for AF ablation.

Relation of morbid obesity and female gender to risk of procedural complications in patients undergoing atrial fibrillation ablation.

Obese patients with atrial fibrillation (AF) are frequently treated with AF ablation. We sought to examine whether a body mass index (BMI) threshold exists beyond which the odds of experiencing a complication from AF ablation increases. All patients enrolled in the Vanderbilt AF Registry who underwent catheter-based AF ablation from May 1999 to February 2012 were included. Major complications were recorded. Morbid obesity was defined as a BMI >40 kg/m(2) and examined in multivariable analysis. A total of 35 complications (6.8%) occurred in 512 ablations. Morbidly obese patients experienced a greater rate of complications (6 of 42, 14.3%) than the nonmorbidly obese (29 of 470, 6.2%; p = 0.046). Using a discrete BMI cutoff, the odds of complications increased 3.1-fold in those with morbid obesity (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.1 to 8.4, p = 0.03) and 2.1-fold for female gender (OR 2.1, 95% CI 1.04 to 4.38, p = 0.04). With BMI as a continuous variable, the odds of complications increased by 5% per 1 unit increase in BMI (OR 1.05, 95% CI 1.0 to 1.11, p = 0.05), and the increase for female gender was 2.2-fold (OR 2.2, 95% CI 1.1 to 4.6, p = 0.03). In conclusion, morbid obesity represents a BMI threshold above which the odds of complications with AF ablation increase significantly. The increase in complications appears to be driven primarily by events in women, suggesting that morbidly obese women are a special population when considering AF ablation.

Learning curve in transradial cardiac catheterization: procedure-related parameters stratified by operators' transradial volume.

OBJECTIVE: To determine whether radial artery access is associated with a reduction in fluoroscopy time, procedure time, and other procedural variables over a 27-month period during which the radial artery approach was incorporated in a single academic Medical Center. BACKGROUND: Although previous studies have demonstrated a relationship between increased volume and decreased procedural time, no studies have looked at the integration of radial access over time. METHODS: Data were collected from consecutive patients who presented to the Vanderbilt University Medical Center cardiac catheterization laboratory from January 1, 2009 to April 1, 2011. Patients who underwent radial access diagnostic catheterization with and without percutaneous coronary intervention were included in this study. A total of 1112 diagnostic cardiac catheterizations through the radial access site were analyzed. High-volume, intermediate-volume, and low-volume operators were grouped based on the percentage of procedures performed through a radial approach. RESULTS: From 2009 to 2011, there was a significant decrease in fluoroscopy time in all operator groups for diagnostic catheterization (P=.035). The high-volume operator group had 1.88 and 3.66 minute reductions in fluoroscopy time compared to the intermediate- and low-volume operator groups, respectively (both P<.001). Likewise, the intermediate-volume operator group had a 1.77 minute improvement compared to the low-volume operator group, but this did not reach statistical significance (P=.102). The improvement in fluoroscopy time and other procedure-related parameters was seen after approximately 25 cases with further improvement after 75 cases. CONCLUSIONS: The incorporation of the radial access approach in the cardiac catheterization laboratory led to a decrease in fluoroscopy time for each operator and operator group over the last 3 years. Our data demonstrated that higher-volume radial operators have better procedure, room, and fluoroscopy times when compared to intermediate- and low-volume operators. However, lower-volume operators have a reduction in procedure-related parameters with increased radial cases. Number of procedures needed to become sufficient was demonstrated in the current study.

Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation.

OBJECTIVES: This study tested the hypothesis that response to antiarrhythmic drugs (AADs) is modulated by 3 common loci associated with atrial fibrillation (AF). BACKGROUND: Recent genome-wide association studies have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone AF. These findings indicate that variable mechanisms contribute to AF susceptibility, and suggest that response to therapy may be genotype dependent. METHODS: We studied 478 and 198 Caucasian patients in the discovery cohort and validation cohort, respectively, who were prospectively enrolled in the Vanderbilt AF registry. Response was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥75% reduction in symptomatic AF burden. We also evaluated AF recurrence by 12-lead electrocardiogram (ECG) at 3, 6, and 12 months. Symptomatic patients were also given a 24- to 48-h Holter monitor or 30-day event recorder when AF recurrence was not captured by 12-lead ECG. RESULTS: In the discovery cohort, 399 (83%) patients were successfully rhythm controlled. Multiple clinical variables (including age, hypertension, lone AF) failed to significantly predict response to AADs; however, single nucleotide polymorphism (SNP) rs10033464 at 4q25 was an independent predictor of successful rhythm control in patients with typical AF carrying the ancestral allele (wild type) versus carriers of variant allele (odds ratio [OR]: 4.7, 95% confidence interval [CI]: 1.83 to 12, p = 0.0013. In the validation cohort, 143 (72%) patients met the criteria for successful rhythm control, and rs10033464 was again an independent predictor of successful rhythm control, OR: 1.5, 95% CI: 1.02 to 3.06, p = 0.04. This SNP (rs10033464) was an independent predictor of AF recurrence in the discovery (39% AF recurrence) and validation (38% AF recurrence) cohorts; OR: 3.27, 95% CI: 1.7 to 6, p < 0.001 and OR: 4.3, 95% CI: 1.98 to 9.4, p < 0.001, respectively. CONCLUSIONS: These results suggest that a common SNP on chromosome 4q25 associated with AF modulates response to AAD therapy and points to a potential role for stratification of therapeutic approaches by genotype.

Relation of the severity of obstructive sleep apnea in response to anti-arrhythmic drugs in patients with atrial fibrillation or atrial flutter.

Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected subjects and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether the severity of OSA influences the efficacy of antiarrhythmic drug (AAD) therapy in patients with OSA and AF. The aim of this study was to examine the impact of OSA severity on the treatment of patients with symptomatic AF using AADs. Sixty-one patients (mean age 62 ± 15 years, 21 women) treated with AADs for symptomatic AF who underwent overnight polysomnography were studied. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for ≥6 months with ≥75% reduction in symptomatic AF burden. Twenty-four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Nonresponders to AADs were more likely to have severe OSA than milder disease (52% vs 23%, p <0.05); those with severe OSA were less likely to respond to AADs than participants with nonsevere OSA (39% vs 70%, p = 0.02). Nonresponders had higher apnea-hypopnea indexes than responders (34 ± 25 vs 22 ± 18 events/hour, p = 0.05), but there were no differences between these groups in minimum oxygen saturation or percentage of time spent in rapid eye movement sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA.

A common ß1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation.

OBJECTIVES: In this study, we evaluated the impact of 2 common ß1-adrenergic receptor (ß1-AR) polymorphisms (G389R and S49G) in response to ventricular rate control therapy in patients with atrial fibrillation (AF). BACKGROUND: Randomized studies have shown that ventricular rate control is an acceptable treatment strategy in patients with AF. However, identification of patients who will adequately respond to rate-control therapy remains a challenge. METHODS: We studied 543 subjects (63% men; age 61.8 ± 14 years) prospectively enrolled in the Vanderbilt AF registry and managed with rate-control strategy. A "responder" displayed adequate ventricular rate control based on the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) criteria: average heart rate (HR) at rest ≤80 beats/min; and maximum HR during a 6-min walk test ≤110 beats/min or average HR during 24-h Holter ≤100 beats/min. RESULTS: A total of 295 (54.3%) patients met the AFFIRM criteria. Baseline clinical characteristics were similar in responders and nonresponders except for mean resting HR (76 ± 20 beats/min vs. 70 ± 15 beats/min; p < 0.01) and smoking (6% vs. 1%; p < 0.01). Multiple clinical variables (age, gender, hypertension) failed to predict response to rate-control therapy. By contrast, carriers of Gly variant at 389 were more likely to respond favorably to rate-control therapy; 60% versus 51% in the Arg389Arg genotype, p = 0.04. This association persisted after correction for multiple clinical factors (odds ratio: 1.42, 95% confidence interval: 1.00 to 2.03, p < 0.05). Among responders, subjects carrying the Gly389 variant required the lowest doses of rate-control medications; atenolol: 92 mg versus 68 mg; carvedilol: 44 mg versus 20 mg; metoprolol: 80 mg versus 72 mg; diltiazem: 212 mg versus 180 mg, and verapamil: 276 mg versus 200 mg, respectively (p < 0.01 for all comparisons). CONCLUSIONS: We have identified a common ß1-AR polymorphism, G389R, that is associated with adequate response to rate-control therapy in AF patients. Gly389 is a loss-of-function variant; consequently, for the same adrenergic stimulation, it produces reduced levels of adenyl cyclase, and hence, attenuates the ß-adrenergic cascade. Mechanistically, the effect of rate-control drugs will be synergistic with that of the Gly389 variant, which could possibly explain our findings. These findings represent a step forward in the development of a long-term strategy of selecting treatment options in AF based on genotype.

The "missing" link in atrial fibrillation heritability.

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, represents a major health burden to individuals and health care system within the Western world. The lifetime risk for the development of AF at age 40 years has been estimated to be approximately 1 in 4. Atrial fibrillation is associated with substantial morbidity and a 2-fold increased risk of mortality. Given its increasing prevalence with age, coupled with the aging population, the number of Americans affected with AF is expected to increase from approximately 2.3 million in the year 2000 to nearly 16 million by 2050. This AF epidemic is further complicated by the lack of highly effective therapies. One reason for the lack of effective therapies for AF stems from incomplete understanding of the complex pathophysiology of the arrhythmia. Atrial fibrillation has often been regarded as a condition that occurs in the context of atrial electrical and structural remodeling that can result from cardiac and systemic disorders. However, up to 30% of patients have no obvious cause and are said to have idiopathic or "lone" AF. Up until recently, AF was considered to be a sporadic, nongenetic disorder, but we and others have shown that lone AF has a substantial genetic basis. Mutations in genes encoding cardiac ion channels (KCNQ1, KCNE1-5, KCNJ2, KCNA5, and SCN5A), gap junctions (GJA5), and signaling molecules (atrial natriuretic peptide, nucleoporins [NUP155]) have been reported in isolated cases and small kindreds. The advent of the human genome and HapMap projects and high-throughput genotyping has fundamentally accelerated our ability to discover the genetic contribution to common variation in human disease. In 2007, a genome-wide association study identified 2 genetic variants that associated with AF. More recently, 2 additional AF loci on chromosomes 16q22 and 1q21 have been identified. It is quite likely, however, that the effects of alleles in many genes contribute to common complex diseases such as AF. The overall AF risk associated with common variants identified by the genome-wide association study approach is small (odds ratios, 1.1-2.5) and explains less than 10% of the heritability in lone AF. This raises the possibility that rare independent variants with large effects strong effects may account for a large fraction of the risk for lone AF.

Milk alkali and hydrochlorothiazide: a case report.

Hypercalcemia is a relatively common clinical problem in both outpatient and inpatient settings. Primary pathophysiology is the entry of calcium that exceeds its excretion into urine or deposition in bone into circulation. Among a wide array of causes of hypercalcemia, hyperparathyroidism and malignancy are the most common, accounting for greater than 90 percent of cases. Concordantly, there has been a resurgence of milk-alkali syndrome associated with the ingestion of large amounts of calcium and absorbable alkali, making it the third leading cause of hypercalcemia (Beall and Scofield, 1995 and Picolos et al., 2005). This paper centers on a case of over-the-counter calcium and alkali ingestion for acid reflux leading to milk alkali with concordant use of thiazide diuretic for hypertension.

A rare variant in MYH6 is associated with high risk of sick sinus syndrome.

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²9. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

Lone AF - Etiologic Factors and Genetic Insights into Pathophysiolgy.

Ever since atrial fibrillation (AF) was first recognized in young people (so called "lone" AF) over 4 decades ago, there has been increasing focus on determining the underlying pathophysiology of the condition. Although lone AF is presumed to be a highly heterogeneous disease, recent studies have identified novel risk factors such as inflammation, oxidative stress, endurance sports and genetics, for the arrhythmia. This monograph aims to highlight some of the recent advances in our understanding of the molecular pathophysiology of lone AF especially insight provided by contemporary genetic studies. These insights may provide novel therapeutic targets for treatment of this challenging arrhythmia in young patients.

Long-term outcomes after catheter ablation of cavo-tricuspid isthmus dependent atrial flutter: a meta-analysis.

BACKGROUND: Despite the success of catheter ablation of cavotricuspid isthmus-dependent atrial flutter (AFL), important postablation outcomes are ill-defined. The purpose of our study was to analyze long-term outcomes after catheter ablation of cavotricuspid isthmus-dependent AFL. METHODS AND RESULTS: A meta-analysis was performed of articles reporting clinical outcomes after catheter ablation of AFL published between January 1988 and July 2008. The analysis included 158 studies comprising 10 719 patients (79% men, 59.8+/-0.5 years old, 46% left atrial enlargement, 46% heart disease, 42% with history of atrial fibrillation, 14.3+/-0.4 months of follow-up). The overall acute success rate adjusted for reporting bias was 91.1% (95% CI, 89.5 to 92.4), 92.7% (95% CI, 90.0 to 94.8) for 8- to 10-mm tip/or irrigated radiofrequency catheters, and 87.9% (95% CI, 84.2 to 90.9) for 4- to 6-mm tip catheters (P>0.05). Atrial flutter recurrence rates were significantly reduced by use of 8- to 10-mm tip or irrigated radiofrequency catheters (6.7% versus 13.8%, P<0.05) and by use of bidirectional cavotricuspid isthmus block as a procedural end point (9.3% versus 23.6%, P<0.05). The AFL recurrence rate did not increase over time. The overall occurrence rate of atrial fibrillation after AFL ablation was 33.6% (95% CI, 29.7 to 37.3) but was 52.7% (95% CI, 47.8 to 57.6) in patients with a history of atrial fibrillation before ablation and 23.1% (95% CI, 17.5 to 29.9) in those without atrial fibrillation before ablation (P<0.05). The incidence of atrial fibrillation increased over time in both groups; however, 5 years after ablation, the incidence of atrial fibrillation was similar in those with and without atrial fibrillation before ablation. The acute complication rate was 2.6% (95% CI, 2 to 3). The mortality rate during follow-up was 3.3% (95% CI, 2.4 to 4.5). Antiarrhythmic drug use after ablation was 31.6% (95% CI, 25.6 to 37.8). The long-term use of coumadin was 65.9%, (95% CI, 43.8 to 82.8). Quality of life data were very limited. CONCLUSIONS: AFL ablation is safe and effective. Ablation technology and procedural end points have greater influences on AFL recurrences than on acute ablation success rates. Atrial fibrillation is common after AFL ablation. Almost one third of patients take antiarrhythmic drugs after AFL ablation. Atrial fibrillation before AFL ablation may indicate a more advanced state of electric disease.

Effect of electrode orientation on lesion sizes produced by irrigated radiofrequency ablation catheters.

BACKGROUND: Irrigated radiofrequency (RF) ablation catheters may produce different lesion sizes dependent upon the electrode orientation to the tissue. This study examined the effect of irrigated electrode orientation on the lesion size and explores a potential mechanism for this effect. METHODS AND RESULTS: Lesions were created in isolated porcine myocardium using an open irrigation, closed irrigation, and nonirrigated RF catheter (all 3.5-4 mm tips). Lesions were created with the electrodes with all permutations of electrode orientation (vertical or horizontal), contact pressure (6 or 20 g), and saline superfusate flow (0.2 or 0.4 m/sec) over tissue interface. The effect of electrode irrigation without RF delivery on tissue temperature was assessed with intramyocardial temperature probes and infrared thermal imaging. For both irrigated catheters, the horizontal orientation produced 25-30% smaller lesion volumes than the vertical orientation despite equal or greater power deliveries. The horizontal orientation produced larger lesion volumes for the nonirrigated catheter. Higher superfusate flow rates were associated with decreased lesion volumes for the irrigated catheters but greater lesion volumes for the nonirrigated catheter. Catheter irrigation alone without RF delivery reduced intramyocardial temperatures up to 4.9 degrees C and the horizontal orientation produced a 2-fold greater area of tissue cooling than the vertical orientation. CONCLUSION: Horizontal electrode orientations reduce lesion volumes for irrigated RF catheters. This effect may be in part due to greater areas of active tissue cooling in the horizontal orientation.