Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke.

Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

AIMS: The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS: We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS: AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

Hostility, metabolic syndrome, inflammation and cardiac control in young adults: The Young Finns Study.

We studied whether there is an association between hostility and cardiovascular heart disease (CHD) risk factors, such as the metabolic syndrome, systemic inflammation and autonomic cardiac control. Participants were 912 women and 712 men aged 15-30 when hostility was measured in 1992. Metabolic syndrome was assessed 9years later in 2001 using 3 definitions: the National Institute of Health Adult Treatment Panel III criteria (NCEP), the European Group for the Study of Insulin Resistance criteria (EGIR), and the International Diabetes Federation criteria (IDF). C-reactive protein (CRP) defined in 2001 was the marker of inflammation. Cardiac control indices were from EGC recording. In women, hostility predicted increased risk of metabolic syndrome (EGIR, and the IDF definitions, ORs = 1.34, 1.35, p < 0.05), and higher levels of inflammation (ß = 0.09, p < 0.01). We concluded that hostility is associated with metabolic syndrome and systemic inflammation in women and these conditions may be factors linking hostility to CHD.

Heart rate variability is independently associated with C-reactive protein but not with Serum amyloid A. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Increased levels of C-reactive protein (CRP) and serum amyloid A (SAA) are associated with an increased risk of cardiovascular disease. It is hypothesized that dysregulation of the autonomic nervous system (ANS) leads to increased inflammation via the cholinergic anti-inflammatory pathway. Heart rate variability (HRV) is a marker of ANS function. HRV has been shown to be associated with CRP levels. Currently, there are no studies addressing the relationship between HRV and SAA. DESIGN: The purpose of this study was to compare the associations between HRV, CRP and SAA in healthy young adults. CRP and SAA concentrations and short-term HRV indices [high frequency (HF), low frequency (LF), total spectral component of HRV, root mean square differences of successive R-R intervals, the standard deviation of all R-R intervals and ratio between LF and HF) were measured in 1601 men and women aged 24-39 taking part in the Cardiovascular Risk in Young Finns study. RESULTS: A significant inverse correlation (P < 0·05) between HRV indices and inflammatory markers was observed. However, in linear regression analyses, only inverse association between HRV indices and CRP levels remained significant (P < 0·05), while association between HRV indices and SAA levels was attenuated to the null (P > 0·05) after adjusting for age, sex, body mass index, cholesterol levels, leptin and other common traditional cardiovascular risk factors. CONCLUSIONS: Reduced HRV indices are independently associated with increased CRP levels, but not with SAA levels. This association supports the hypothesis that dysregulation of the ANS may lead to increased inflammation early in adulthood.

Relations between carotid artery distensibility and heart rate variability The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Reduction in carotid artery wall elasticity may interfere with baroreceptor function that could lead to low vagal tone. We studied at the population level the relations between carotid-artery-distensibility (Cdist) and vagal modulation of heart rate. METHODS AND RESULTS: Cdist was assessed with ultrasonic measurements of changes in carotid artery diameter during cardiac-cycle. Vagal tone was estimated with the heart rate variability (HRV) in 1872 healthy 24-39year-old subjects. Cdist was significantly related with all HRV-components (always P<0.0001). After adjustments with sex, age and heart rate, we found statistically significant correlation between Cdist and the high-frequency component (HF, estimate of vagal-tone) of HRV (P<0.05). An inverse association between the number of cardiovascular risk-factors and vagal-tone was seen in subjects with less elastic arteries, but not in subjects with more elastic arteries (P for interaction=0.01). CONCLUSIONS: These data support the hypothesis that reduction in carotid artery wall elastic properties may lead to low vagal tone. Furthermore, carotid distensibility seemed to modify the relation between risk-factors and HRV. Increased cardiovascular risk associated with low vagal tone may partly be mediated via changes in carotid artery elastic properties.

Short-term heart rate variability in healthy young adults: the Cardiovascular Risk in Young Finns Study.

Reduced short-term heart rate variability (HRV) is a risk factor for cardiovascular morbidity and total mortality. The reference values of short-term HRV indices in healthy young adults are unknown. To investigate age and sex differences in HRV and to generate reference values of short-term recordings, we examined 1780 healthy subjects aged 24 to 39 years. Both frequency and time domain HRV indices were computed. Indices included; low frequency (LF), high frequency (HF) and total components of spectral-HRV, the square root of mean squared differences of R-R-intervals and SD of normal R-R-intervals. Deep breathing test was performed and the mean ratio of R-R-intervals and the mean difference in instantaneous heart rate during breathing cycle were analyzed. Reproducibility of these indices was studied in 43 subjects. Aging and higher heart rate were inversely associated with all HRV indices (all p values <0.0001). Women had higher HF and lower LF compared to men (both p<0.0001). Women had higher resting heart rate (70 vs. 65 bpm, p<0.0001). The reproducibility of HRV indices and deep breathing test were good (CV 5.3-13.9%). We conclude that age, sex and heart rate needs to be considered when evaluating HRV indices and when generating reference values. Because of good reproducibility the short-term indices of HRV and deep breathing test can be used in clinical work.

Common variation in NOS1AP and KCNH2 genes and QT interval duration in young adults. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Common genetic variants in the nitric oxide synthase 1 adaptor protein gene (NOS1AP) and in the HERG potassium channel gene (KCNH2) have been associated with cardiac repolarization in middle-aged and elderly subjects. AIM: We examined the relation between these variants and QT interval duration in a population of healthy young adults. METHODS: We measured QT interval duration and genotyped rs10494366 T>G (NOS1AP gene, n=1,842) and rs1805123 A>C (KCNH2 gene, n=1,894) in subjects aged 24-39 years. RESULTS: The NOS1AP variant was significantly related with heart rate-corrected QT interval duration (QTc). Additive regression model adjusting for age, sex, systolic blood pressure, body mass index, alcohol use, and smoking indicated that the G allele was associated with a 3.2 ms (95% confidence interval (CI) 1.7-4.6 ms, P<0.0001) increase in QTc interval duration for each additional copy. The KCNH2 variant was not significantly related with QTc interval duration in the study sample. CONCLUSION: These findings provide evidence from a population of healthy young adults that a common variation in the NOS1AP gene influences cardiac repolarization within the normal physiological range. Further studies are warranted to investigate the effects of this variant on sudden cardiac death and ventricular arrhythmias.

Temperament, health-related behaviors, and autonomic cardiac regulation: the cardiovascular risk in young Finns study.

Temperament, as indicated by Cloninger's psychobiological model predicts coronary heart disease risk, but its association with autonomic cardiac regulation, a potential mediating mechanism, is unclear. We examined the associations between temperament traits and autonomic cardiac regulation in a resting situation in 798 women and 580 men derived from a population-based sample. After adjustment for age and sex, harm avoidance was associated with lower level of high-frequency (HF) variation, root mean square successive differences (RMSSDs), the percentage of successive R-R intervals>50 ms (pNN50) and higher heart rate (HR) (all p

Effort-reward imbalance, heart rate, and heart rate variability: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Work stress indicated by effort-reward imbalance is hypothesized to cause autonomic arousal, which, if prolonged or frequent, could contribute to cardiovascular pathology. However, only limited empirical evidence on this mechanism is available. PURPOSE: This study examined associations between effort-reward imbalance, heart rate (HR), and heart rate variability (HRV). METHOD: The participants were 457 women and 406 men (mean age 32.3 years) derived from the population-based Young Finns Study. Effort-reward imbalance was defined as the ratio between effort and reward, higher efforts compared to rewards indicating greater imbalance. RESULTS: In age-adjusted regression models, higher effort-reward imbalance was associated with lower HRV, and lower reward was associated with higher HR among women. These associations were not attenuated after additional adjustments for demographic characteristics and coronary risk factors. No significant associations of effort-reward imbalance or its components with HR and HRV were found in men. CONCLUSION: Our finding of lower HRV and higher HR in young healthy women with high effort-reward imbalance and low rewards provides evidence of a potential mechanism that may link effort-reward imbalance to the development of coronary heart disease (CHD) in women.