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.

Arrhythmogenic Munchausen syndrome culminating in caffeine-induced ventricular tachycardia.

We report a patient with numerous abnormal electrocardiograms (ECGs) in both inpatient and outpatient settings. Our patient both simulated and stimulated her arrhythmias with an ECG rhythm generator and intentional caffeine intoxication. To our knowledge, this is the first report of caffeine overdose for arrhythmogenesis.

Clinical characteristics and outcomes of patients with hypertrophic cardiomyopathy with latent obstruction.

BACKGROUND: The purpose of this article is to describe the demographic and clinical features of patients with hypertrophic cardiomyopathy (HCM) and latent obstruction, with an emphasis on identifying factors associated with disease progression and survival. The presence of a resting left ventricular outflow obstruction in patients with HCM has been well described and is associated with increased symptoms and adverse long-term outcomes. However, less is known about patients with latent obstruction. METHODS: Four hundred fifteen patients with echocardiographic or catheterization findings of latent obstruction, defined as a left ventricular outflow pressure gradient <30 mm Hg at rest, which increases to > or =30 mm Hg with provocation, were identified and included in the study group. RESULTS: The mean age was 55.0 +/- 17.9, and 226 (54.6%) patients were male. There were 330 (79.5%) patients with New York Heart Association (NYHA) functional class I and II at baseline. Fifty-nine (17.9%) of these patients had symptom progression requiring septal reduction therapy. Eighty-five patients had severe symptoms (NYHA functional class III and IV) at baseline, and 23 (27.1%) underwent septal reduction. Overall survival at 1, 5, and 10 years was 98%, 91%, and 81%, respectively. Survival among patients after undergoing invasive relief of outflow obstruction was equivalent to the general US population. CONCLUSIONS: Latent obstruction in HCM is an important pathophysiologic entity and may cause heart failure symptoms. One-third of patients in this referral series required invasive therapy for relief of symptoms. The evaluation of HCM patients with resting outflow tract gradients <30 mm Hg must include provocative maneuvers to identify this substantial subset of patients, preferably by physiologic exercise.

Ambulatory monitoring of aborted sudden cardiac death related to hypertrophic cardiomyopathy.

BACKGROUND: A 47-year-old woman with obstructive hypertrophic cardiomyopathy presented with chest pain that had persisted despite treatment with verapamil and alpha-receptor antagonists. The patient had no other significant cardiac symptoms, no history of hypertension, and no familial predisposition to hypertrophic cardiomyopathy or sudden cardiac death. A loud (grade III/VI), dynamic, systolic ejection murmur was noted that could be heard diffusely over the precordium. INVESTIGATIONS: Radionuclide perfusion imaging, coronary angiography, intracoronary Doppler flow measurements, and ambulatory electrocardiographic monitoring. DIAGNOSIS: Obstructive hypertrophic cardiomyopathy, myocardial ischemia and sudden cardiac arrest. MANAGEMENT: Surgical myectomy and cardioverter-defibrillator implantation.

Relation of anemia at discharge to survival after acute coronary syndromes.

Two-year survival rate was assessed among 1,038 patients who had acute coronary syndromes that were classified by discharge hematocrit values as normal (>39%, n = 360, 34.7%), mildly anemic (33.1% to 39%, n = 430, 41.4%), or moderately/severely anemic (< or = 33%, n = 248, 23.9%). Worsening anemia was associated with a decreased 2-year survival rate (normal 95.8%, mild anemia 91.2%, moderate/severe anemia 81.5%, p < 0.001). In multivariable analyses, adjusted hazard ratios for all-cause mortality were 1.57 (95% confidence interval 0.82 to 2.96) for mild anemia and 2.46 (95% confidence interval 1.25 to 4.85) for moderate/severe anemia.

Testing the performance of the ENRICHD Social Support Instrument in cardiac patients.

BACKGROUND: Previous investigations suggest an important role of social support in the outcomes of patients treated for ischemic heart disease. The ENRICHD Social Support Instrument (ESSI) is a 7-item self-report survey that assesses social support. Validity and reliability of the ESSI, however, has not been formally tested in patients undergoing percutaneous coronary intervention (PCI). METHODS: The ESSI, along with the Short Form-36 (SF-36), was sequentially administered to a cohort of 271 patients undergoing PCI. The test-retest reliability was examined with an intra-class correlation coefficient by comparing scores among 174 patients who completed both instruments 5 and 6 months after their procedure. Internal reliability was assessed using Cronbach's alpha at the time of patients' baseline procedure. The concurrent validity of the ESSI was assessed by comparing scores between depressed (MHI-5 score < 44) vs. non-depressed patients. The correlation between the ESSI and the SF-36 Social Functioning sub-scale, an accepted measure of social functioning, was also examined. RESULTS: Test-retest reliability showed no significant differences in mean scores among ESSI questionnaires administered 1 month apart (27.8+/-1.4 vs 27.8+/-1.5, p = 0.98). The intra-class correlation coefficient was 0.94 and Cronbach's alpha was 0.88. Mean ESSI scores were significantly lower among depressed vs. non-depressed patients (24.6+/-1.7 vs 27+/-1.4, p < 0.018) and a positive albeit modest correlation with social functioning was seen (r = 0.19, p = 0.002). CONCLUSION: The ESSI appears to be a valid and reliable measure of social support in patients undergoing treatment for coronary artery disease. It may prove to be a valuable method of controlling for patient variability in outcomes studies where the outcomes are related to patients' social support.