Impact of Voltage Mapping to Guide Whether to Perform Ablation of the Posterior Wall in Patients With Persistent Atrial Fibrillation.

BACKGROUND: Fibrosis as a substrate for atrial fibrillation (AF) has been shown in numerous preclinical models. Voltage mapping enables in vivo assessment of scar in the left atrium (LA), which can be targeted with catheter ablation. OBJECTIVE: We hypothesized that using the presence or absence of low voltage to guide ablation beyond pulmonary vein antral isolation (PVAI) will improve atrial arrhythmia (AF/AT)-free survival in persistent AF. METHODS AND RESULTS: Single-center retrospective analysis of 2 AF ablation strategies: (1) standard ablation (SA) versus (2) voltage-guided ablation (VGA). PVAI was performed in both groups. With SA, additional lesions beyond PVAI were performed at the discretion of the operator. With VGA, additional lesions to isolate the LA posterior wall were performed if voltage mapping of this region in sinus rhythm showed scar (LA voltage < 0.5 mV). AF-/AT-free endpoint was defined as no sustained AF/AT seen off antiarrhythmic medications after a 2-month postablation blanking period. Seventy-six patients underwent SA and 65 underwent VGA. Patients were well matched for comorbidities, LVEF, and left atrial size. Posterior wall ablation was performed in 57% of patient with SA compared to 42% with VGA. VGA ablation increased 1-year AF-/AT-free survival in patients when compared to SA (80% vs. 57%; P = 0.005). In a multivariate analysis, VGA was the only independent predictor of AF-/AT-free survival (hazard ratio of 0.30; P = 0.002). CONCLUSIONS: The presence of LA posterior wall scar may be an important ablation target in persistent AF. A prospective randomized trial is needed to confirm these data.

Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation.

OBJECTIVES: The aim of this study was to test the hypothesis that 2 common polymorphisms in the chromosome 4q25 region that have been associated with atrial fibrillation (AF) contribute to the variable penetrance of familial AF. BACKGROUND: Although mutations in ion channels, gap junction proteins, and signaling molecules have been described for Mendelian forms of AF, penetrance is highly variable. Recent studies have consistently identified 2 common single-nucleotide polymorphisms in the chromosome 4q25 region as independent AF susceptibility alleles. METHODS: Eleven families in which AF was present in ≥2 members who also shared a candidate gene mutation were studied. These mutations were identified in all subjects with familial lone AF (n = 33) as well as apparently unaffected family members (age >50 years with no AF; n = 17). RESULTS: Mutations were identified in SCN5A (n = 6), NPPA (n = 2), KCNQ1 (n = 1), KCNA5 (n = 1), and NKX2.5 (n = 1). In genetic association analyses, unstratified and stratified according to age of onset of AF and unaffected age >50 years, there was a highly statistically significant association between the presence of both common (rs2200733 and rs10033464) and rare variants and AF (unstratified p = 1 × 10(-8), stratified [age of onset <50 years and unaffected age >50 years] p = 7.6 × 10(-5)) (unstratified p < 0.0001, stratified [age of onset <50 years and unaffected age >50 years] p < 0.0001). Genetic association analyses showed that the presence of common 4q25 risk alleles predicted whether carriers of rare mutations developed AF (p = 2.2 × 10(-4)). CONCLUSIONS: Common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with familial AF. These findings support the idea that the genetic architecture of AF is complex and includes both rare and common genetic variants.

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.

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.

Physician awareness of the cardiac effects of methadone: results of a national survey.

BACKGROUND: Levacetylmethadol was withdrawn from the U.S. market as a treatment for opioid-dependent patients in 2003 due to QT prolongation, leaving methadone as the primary therapy for over 200,000 individuals. Methadone was subsequently shown to prolong the QT interval as well. We hypothesized that opioid treatment program physicians are unaware of these safety concerns. METHODS: To assess awareness of methadone's QT-prolonging properties, we conducted a national mail survey of physicians licensed as medical directors for accredited U.S. opioid treatment programs in 2006. The primary outcome was knowledge of methadone's QT-prolonging effects. Awareness of the cardiac effects of levacetylmethadol and buprenorphine were also assessed. RESULTS: The survey response rate was 66% (692 physicians) of whom 35% were family practitioners, 25% internists, 22% psychiatrists, and 8% self-identified as addiction specialists. While 75% (95% CI, 72-78) correctly identified levacetylmethadol as a QT-prolonging drug, only 41% (95% CI, 37- 45) were aware of methadone's QT-prolonging properties. Just 24% (95% CI, 21-27) were aware of methadone's association with torsade de pointes. In addition, 52% (95% CI, 48- 56) correctly reported the absence of an association between buprenorphine and QT prolongation. Larger program census and academic setting tended to predict greater awareness of methadone's QT-prolonging effects; yet even in these subgroups awareness did not exceed 54%. CONCLUSIONS: Scientific publication alone has been inadequate in raising awareness regarding methadone's QT-prolonging properties, even among those who most often prescribe the drug. Universal education initiatives for all accredited opioid treatment programs seem warranted to enhance the safety of this essential therapy.

Trends in anticoagulation for atrial fibrillation in the U.S.: an analysis of the national ambulatory medical care survey database.

OBJECTIVES: The purpose of this study was to track trends in the use of anticoagulation for atrial fibrillation (AF) over the past decade and identify predictors of use. BACKGROUND: Atrial fibrillation is common and associated with significant morbidity. Previous studies suggest underuse of anticoagulant therapy in patients with AF. METHODS: The National Ambulatory Medical Care Survey database was queried for all patient visits with a diagnosis of AF between 1994 and 2003. Other diagnoses, other medications, and demographic, visit, geographic, and provider characteristics were compared with the prescription of anticoagulation in predefined age and risk groups. RESULTS: The prevalence of the diagnosis of AF and anticoagulation for AF has increased over the last decade. Increased age and use of rate control agents is associated with the use of anticoagulation. There is a trend toward less anticoagulation when a rhythm control agent is used instead of a rate control agent. Anticoagulation might be overused in a group of low-risk patients. CONCLUSIONS: From 1995 through 2002, an increase has occurred in anticoagulation for AF, especially in those at highest risk for thromboembolic phenomena. A substantial number of patients at risk for thromboembolic events are not anticoagulated, and further studies are needed to determine how many of these patients are candidates for anticoagulation. Anticoagulation use has increased in nontargeted, low-risk groups in whom antiplatelet agents are appropriate. Use of a rhythm control agent might be associated with less use of anticoagulation.

Paradoxical decrease in blood pressure after relief of cardiac tamponade: the role of sympathetic activity.

BACKGROUND: In contrast to patients who develop acute cardiac tamponade after penetrating trauma, tamponade in medical patients may be accompanied by normal or even elevated systolic blood pressure. This has been attributed to heightened sympathetic nervous system activity. CASE REPORT: We present a case of a medical patient with simultaneous hypertension and cardiac tamponade whose blood pressure fell dramatically after pericardiocentesis. We observed a decrease in normetanephrine levels in our patient concomitant with the decrease in blood pressure. CONCLUSIONS: Our case provides further support for involvement of the sympathetic nervous system in medical patients with hypertensive tamponade. To our knowledge, this is the first case documenting adrenergic status in a patient with a paradoxical decrease in blood pressure after relief of tamponade.

Cocaine-related torsade de pointes in a methadone maintenance patient.

A patient maintained on methadone for opioid-dependency developed recurrent syncope. Episodes occurred within hours after using cocaine, and were initially presumed secondary to seizure disorder. However, the patient subsequently suffered a cardiac arrest, and polymorphic ventricular tachycardia (torsade de pointes) was documented. Other than cocaine and methadone the patient was receiving no additional agents known to prolong the QT interval. Low serum methadone concentrations and marked reversible left ventricular systolic dysfunction were noted during the hospitalization. These findings, in conjunction with a history of torsade de pointes temporally related to cocaine abuse, suggest that cocaine was a major precipitant of arrhythmia. Recent experimental studies have shown that cocaine and methadone prolong the QT interval through the same mechanism. We examine the effects of cocaine and methadone on cardiac conduction in the context of the opioid-dependent population.

A cooperative care model: cardiologists and hospitalists reduce length of stay in a chest pain observation unit.

Chest pain observation units are increasingly used to evaluate patients at low risk for cardiovascular events and are commonly staffed by cardiologists. The role of hospitalists in this setting has not been described. We assessed emergency department (ED) length of stay before and after adding hospitalists to the care team among 493 patients. Prior to intervention, median ED length of stay was 19.3 hours, which decreased to 11.0 hours with the addition of hospitalists (43% decrease, P <0.0001). No significant difference in 30-day cardiac event rate was observed (5% versus 6%, P = 0.68).