Sex Hormones and Ischemic Stroke: A Prospective Cohort Study and Meta-Analyses.

CONTEXT AND OBJECTIVE: Whether endogenous sex hormones are associated with ischemic stroke (IS) is unclear. We tested the hypothesis that extreme concentrations of endogenous sex hormones are associated with risk of IS in the general population. DESIGN, SETTING, AND PARTICIPANTS: Adult men (n = 4615) and women (n = 4724) with measurements of endogenous sex hormones during the 1981-1983 examination of the Copenhagen City Heart Study, Denmark, were followed for up to 29 years for incident IS, with no loss to follow-up. Mediation analyses assessed whether risk of IS was mediated through potential mediators. Present and previous findings were summarized in meta-analyses. MAIN OUTCOME MEASURES: Plasma total testosterone and total estradiol were measured by competitive immunoassays. Diagnosis of IS was ascertained from the national Danish Patient Registry and the national Danish Causes of Death Registry and verified by experienced neurologists. RESULTS: During follow-up, 524 men and 563 women developed IS. Men with testosterone concentrations ≤10th percentile compared to the 11th-90th percentiles had a hazard ratio for IS of 1.34 (95% confidence interval, 1.05-1.72); 21% of this risk was mediated by body mass index (P = .002) and 14% by hypertension (P = .02). In accordance with this, the corresponding hazard ratio was 1.46 (1.09-1.95) in overweight/obese and hypertensive men. The corresponding hazard ratio in the meta-analysis was 1.43 (1.21-1.70). Other extreme concentrations of testosterone or estradiol were not associated with risk of IS in men or women. CONCLUSIONS: Extremely low endogenous testosterone concentrations were associated with high risk of IS in men, a risk mediated in part by body mass index and hypertension. Whether or not low testosterone is a causal factor for IS or merely a biomarker of poor metabolic health is still not known.

Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women.

OBJECTIVE: Sex hormones may be critical determinants of ischemic heart disease and death in women, but results from previous studies are conflicting. To clarify this, we tested the hypothesis that extreme plasma concentrations of endogenous estradiol and testosterone are associated with risk of ischemic heart disease and death in women. APPROACH AND RESULTS: In a nested prospective cohort study, we measured plasma estradiol in 4600 and total testosterone in 4716 women not receiving oral contraceptives or hormonal replacement therapy from the 1981 to 1983 examination of the Copenhagen City Heart Study. During ≤30 years of follow-up, 1013 women developed ischemic heart disease and 2716 died. In women with a plasma estradiol below the fifth percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk of ischemic heart disease was 44% (95% confidence interval, 14%-81%) higher; however, plasma estradiol concentrations did not associate with death. Also, in women with a plasma testosterone concentration at or above the 95th percentile compared with between the 10th and 89th percentiles, multifactorially adjusted risk was 68% (34%-210%) higher for ischemic heart disease, 36% (18%-58%) higher for any death, and 38% (15%-65%) higher for death from other causes than cardiovascular disease and cancer. These results were similar for postmenopausal women alone. CONCLUSIONS: In women, extreme low concentrations of endogenous estradiol were associated with high risk of ischemic heart disease, and extreme high concentrations of endogenous testosterone were associated with high risk of ischemic heart disease and death.

Prevalence of family history in patients with reflex syncope.

Reflex syncope is defined by a rapid transient loss of consciousness caused by global cerebral hypoperfusion resulting from vasodilatation and/or bradycardia attributable to inappropriate cardiovascular reflexes. A hereditary component has been suggested, but prevalence of family history may differ among subtypes of reflex syncope, as these have different autonomic responses and pathogeneses may be diverse. The present study aimed to assess the prevalence of a positive family history of syncope and cardiovascular characteristics in patients with cardioinhibitory and vasodepressor reflex syncope. Patients (n=74) were classified into subtypes of reflex syncope - cardioinhibition/asystole (Vasovagal Syncope International Study subtypes II-B [VASIS II-B], n=38) or vasodepressor (VASIS III, n=36) - using the head-up tilt test. Family history was obtained by questionnaires supplemented by interview. Patients with cardioinhibitory syncope had a mean onset of disease 8 years earlier than vasodepressor patients (mean ± standard deviation 14.5 years ± 12.6 for cardioinhibitory patients compared to 22.4 years ± 11.9 for vasodepressor patients, p<0.001). Thirty-seven (50%) of 74 probands had a positive family history with at least one relative affected with syncope, arrhythmias, known sudden unexpected death, and/or heart disease. The prevalence of a positive family history was higher in patients with cardioinhibitory syncope compared to vasodepressor syncope (24 (63%) compared to 13 (36%); p=0.02). Overall, 40 first-degree relatives (26%) and 27 second- or third-degree relatives (25%) were affected. The most frequent events in families of patients with cardioinhibitory or vasodepressor reflex syncope were severe syncope and/or arrhythmias, known sudden unexpected deaths, and heart disease. In conclusion, prevalence of familial occurrence of syncope is in agreement with previous studies. However, a high occurrence of all-cardiovascular disorders in cardioinhibitory patients may reflect shared genetic susceptibility to these diseases.

Rare variants in GJA5 are associated with early-onset lone atrial fibrillation.

BACKGROUND: Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group. METHODS: The coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios were calculated for different genetic models. RESULTS: Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles). CONCLUSIONS: We show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental.

Differences in autonomic balance in patients with cardioinhibitory and vasodepressor type of reflex syncope during head-up tilt test and active standing.

OBJECTIVE: To improve the pathophysiological understanding of cardioinhibitory and vasodepressor reflex syncope, by evaluating orthostatic effects on electrical and hemodynamic variables. To unravel the pathogeneses further, we studied these effects during both the passive head-up tilt test and the active standing test. BACKGROUND: The current knowledge of the compromised autonomic balance in patients with reflex syncope is limited. The orthostatic responses to head-up tilt test in cardioinhibitory and vasodepressor patients differ, suggesting different pathogeneses; however, the more physiological active standing test represents daily life situations better. METHODS: We included 74 patients; 36 cardioinhibitory and 38 vasodepressor. Patients were compared with respect to vascular hemodynamics and heart rate variability during the change from supine to upright position. Resting electrolytes, brain natriuretic peptide (BNP), pro-atrial natriuretic peptide (pro-ANP), and the C-terminal of pro-vasopressin, copeptin were measured. RESULTS: Resting systolic blood pressure was higher in cardioinhibitory (117.8 ± 15.7 mmHg) than in vasodepressor patients (109.1 ± 15.3 mmHg, p < 0.001). Changes in heart rate tended to be smaller in cardioinhibitory patients (6.7 ± 9.8 vs. 10.7 ± 8.9 bpm, p = 0.056). Heart rate variability was lower and changed less in cardioinhibitory patients (p < 0.05). Cardioinhibitory patients had higher pro-ANP levels (63.5 ± 18.8 pM) compared to vasodepressor patients (54.2 ± 31.4 pM, p = 0.018). Responses during active standing were attenuated compared to head-up tilt in both groups. CONCLUSIONS: This study demonstrated that cardioinhibitory patients had higher blood pressure, attenuated hemodynamic responses, and reduced autonomic regulation compared to vasodepressor patients. Furthermore, cardioinhibitory patients showed a sympathetic predominance in their modulation of autonomic responses. Orthostatic responses induced by active standing were modest and did not sufficiently explain potential pathophysiological differences between cardioinhibitory and vasodepressor patients.

Genetic variation in the inwardly rectifying K channel subunits KCNJ3 (GIRK1) and KCNJ5 (GIRK4) in patients with sinus node dysfunction.

BACKGROUND: Sinus node dysfunction (SND) is a heterogeneous disorder of unknown etiology characterized by a variety of supraventricular arrhythmias with symptoms of syncope, palpitations, and dizziness. The mechanism underlying the abnormal rhythm is incompletely understood. OBJECTIVE: Because vagal stimulation and acetylcholine (ACh) affect the function of pacemaker cells, we hypothesized that genetic variation in the genes encoding the ACh-activated K(+) channels, the KACh channels, could be involved in the pathogenesis of SND. METHODS AND RESULTS: We screened 184 patients listed in the pacemaker registry of the Copenhagen University Hospital aged <60 years at pacemaker implantation for SND in the period 1982-2005. Forty-three patients fulfilled the following inclusion criteria: documented sinus arrest, asystole, or extreme sinus bradycardia. The coding sequences of KCNJ3 and KCNJ5, encoding the main subunits of the KACh channels, were re-sequenced. We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. CONCLUSIONS: Genetic variation in KCNJ3 and KCNJ5 encoding the subunits of the KACh channels is apparently not involved in the pathogenesis of SND.