Lasse Steen Ravn

Familial aggregation of Atrial Fibrillation – a study in Danish Twins

Background— Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results— A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P <0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions— All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF. Received July 1, 2008; accepted April 23, 2009. # CLINICAL PERSPECTIVE {#article-title-2}Background—Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results—A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P<0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions—All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF.

Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.

BACKGROUND Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 beta-subunit, has been shown to reduce IKs. OBJECTIVE The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF. METHODS One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5. RESULTS A missense mutation involving substitution of a phenylalanine for leucine at position 65 (L65F) was identified in one patient. This patient did not have a history of familial AF, and neither KCNQ1 nor KCNE2 mutations were found. Transient transfection of Chinese hamster ovary (CHO) cells expressing IKs(KCNQ1+KCNE1) with KCNE5 suppressed the developing and tail currents of IKs in a concentration-dependent manner. Transient transfection with KCNE5-L65F failed to suppress IKs, yielding a current indistinguishable from that recorded in the absence of KCNE5. Developing currents recorded during a test pulse to +60 mV and tail currents recorded upon repolarization to -40 mV both showed a significant concentration-dependent gain of function in IKs with expression of KCNE5-L65F vs KCNE5-WT. CONCLUSION The results of this study suggest that a missense mutation in KCNE5 may be associated with nonfamilial or acquired forms of AF. The arrhythmogenic mechanism most likely is a gain of function of IKs.

Raised Plasma Aldosterone and Natriuretic Peptides in Atrial Fibrillation

Background and Aims: During atrial fibrillation (AF), the renin-angiotensin-aldosterone system (RAAS) may be activated.In this study, our aim was to evaluate at a long-term follow-up visit the levels of plasma aldosterone and natriuretic peptides as markers of neurohormonal remodeling in patients with earlier, documented AF in relation to present heart rhythm, clinical data, and the left ventricular ejection fraction (LVEF). We hypothesized that increased levels of aldosterone and natriuretic peptides were significantly associated with present AF as markers of RAAS activation during the arrhythmia. Methods: We studied 158 patients with earlier ECG-documented AF followed by restored sinus rhythm (SR) attending a follow-up visit 2.6 years (mean) after primary inclusion. Results: At follow-up, 93 patients had SR. Heart rhythm at follow-up visit (SR/AF), plasma aldosterone, plasma N-terminal pro Brain Natriuretic Peptide (Nt- proBNP), plasma N-terminal pro Atrial Natriuretic Peptide (Nt-proANP), LVEF, medication, and clinical characteristics were recorded. Standard linear multiple regression analysis including age, sex, weight, hypertension, congestive heart failure, ischemic heart disease, present AF at follow-up, total duration of AF disease, ongoing medication, and the LVEF as explanatory variables showed that only ongoing treatment with diuretics was significantly associated (likelihood ratio test, p = 0.0057) with a raised log-transformed plasma aldosterone, although present AF at follow-up was related to a high aldosterone level (p = 0.09). For the natriuretic peptides, present AF at follow-up (p < 0.0001), age (p < 0.0001), female gender (p = 0.0047), ischemic heart disease (p = 0.0154), and ongoing treatment with sotalol (p = 0.0003) were all independently associated with high log-transformed plasma Nt-proANP. Likewise, present AF at follow-up (p = 0.0008) as well as age (p < 0.0001) were associated with high log-transformed plasma Nt-proBNP. Conclusions: In patients with earlier AF, AF at long-term follow-up visit was independently associated with raised levels of Nt-proANP and Nt-proBNP and to some extent with plasma aldosterone indicating neurohormonal activation during arrhythmia.

Angiotensinogen and ACE gene polymorphisms and risk of atrial fibrillation in the general population.

Objectives The renin–angiotensin system may play a role in the pathogenesis of atrial fibrillation, and renin–angiotensin system blockers reduce the risk of atrial fibrillation. We hypothesized that polymorphisms in the angiotensinogen and angiotensin-converting enzyme (ACE) genes encoding proteins in this system predict risk of atrial fibrillation. Methods and results We genotyped 9235 individuals from the Danish general population, The Copenhagen City Heart Study, for the a-20c, g-6a, T174M, and M235T polymorphisms in the angiotensinogen gene and the insertion/deletion (I/D) polymorphism in the ACE gene; rare allele frequencies were 0.16, 0.40, 0.12, 0.41, and 0.49, respectively. Participants had sinus rhythm at inclusion. During 26 years of follow-up, 968 individuals developed atrial fibrillation. Multifactorially adjusted hazard ratios for atrial fibrillation for a-20c ac and cc versus aa genotype were 1.1(95% confidence interval: 1.0–1.3; P=0.05) and 1.5(1.1–2.1; P=0.01). Compared with double noncarriers (angiotensinogen −20aa and ACE II), double heterozygotes (ac-I/D genotype), and double homozygotes (cc-DD) had hazard ratios for atrial fibrillation of 1.2(0.9–1.6; P=0.06) and 2.4(1.4–4.1; P=0.001). a-20c cc homozygotes above 70 years of age who were overweight, severely hypertensive, and had heart failure, had an absolute 10-year risk of atrial fibrillation of 61%. Conclusion Angiotensinogen a-20c genotype alone and in combination with ACE I/D genotype predicts an increased risk of atrial fibrillation. Therefore, genetic variation in the renin–angiotensin system may influence effect of renin–angiotensin system blockers on atrial fibrillation.

Signal-averaged P wave duration and the long-term risk of permanent atrial fibrillation

Objective. To assess the long-term risk of developing permanent AF in relation to the signal-averaged P wave duration (SAPWD) and clinical and echocardiographic characteristics. Design. In an observational study design we studied 131 patients with earlier ECG-documented AF and successfully restored sinus rhythm attending a long-term, follow-up visit at hospital or at home. Established permanent AF was examined in relation to primary clinical, echocardiographic, and electrophysiological parameters. Results. Only prolonged SAPWD (p =0.006) was associated with an increased risk of development of permanent AF. The risk of permanent AF after 3 years follow-up was 0.72 with an SAPWD equal to 180 ms versus 0.39 with a normal SAPWD (130 ms). We found no prognostic effect of age, gender, dilated left atrium, long duration of AF history, or long duration of the most recent episode of AF. Co-existing hypertension reduced the risk of permanent AF; this could be explained by concomitant treatment with angiotensin-converting-enzyme-inhibitors. Conclusion. Prolonged SAPWD (a marker of atrial remodelling) appears to be a risk factor for long-term development of permanent AF.

Familial Aggregation of Atrial FibrillationCLINICAL PERSPECTIVE

Background— Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results— A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P <0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions— All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF. Received July 1, 2008; accepted April 23, 2009. # CLINICAL PERSPECTIVE {#article-title-2}Background—Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results—A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P<0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions—All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF.

Familial Aggregation of Atrial FibrillationCLINICAL PERSPECTIVE: A Study in Danish Twins

Background— Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results— A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P <0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions— All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF. Received July 1, 2008; accepted April 23, 2009. # CLINICAL PERSPECTIVE {#article-title-2}Background—Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. Methods and Results—A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P<0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. Conclusions—All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF.