Telomere Length as a Biomarker for Race-Related Health Disparities.

Disparities between the races have been well documented in health and disease in the USA. Recent studies show that telomere length, a marker of aging, is associated with obesity and obesity-related diseases, such as heart disease and diabetes. The current study aimed to evaluate the connection between telomere length ratio, blood pressure, and childhood obesity. The telomere length ratio was measured in 127 children from both European American (EA) and African American (AA) children, aged 6-10 years old. AA children had a significantly high relative telomere to the single copy gene (T/S) ratio compared to EA children. There was no significant difference in the T/S ratio between normal weight (NW) and overweight/obese (OW/OB) groups of either race. Blood pressure was significantly elevated in AA children with respect to EA children. Hierarchical regression analysis adjusted for race, gender, and age expressed a significant relationship between the T/S ratio and diastolic pressure. Low T/S ratio participants showed a significant increase in systolic pressure, while a high T/S ratio group showed an increase in diastolic pressure and heart rate of AA children. In conclusion, our findings show that AA children have high T/S ratio compared to EA children. The high T/S ratio is negatively associated with diastolic pressure.

Mutant voltage-gated Na+ channels can exert a dominant negative effect through coupled gating.

Mutations in voltage-gated Na+ channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage-gated Na+ channel (Nav)1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel. We also reported that voltage-gated Na+ channels associate as dimers with coupled gating properties. Here, we hypothesized that the dominant negative effect of mutant Na+ channels could also occur through coupled gating. This was tested using cell surface biotinylation and single channel recordings to measure the gating probability and coupled gating of the dimers. As previously reported, coexpression of Nav1.5-L325R with WT channels led to a dominant negative effect, as reflected by a 75% reduction in current density. Surprisingly, cell surface biotinylation showed that Nav1.5-L325R mutant is capable of trafficking, with 40% of Nav1.5-L325R reaching the cell surface when expressed alone. Importantly, even though a dominant negative effect on the Na+ current is observed when WT and Nav1.5-L325R are expressed together, the total Nav channel cell surface expression was not significantly altered compared with WT channels alone. Thus, the trafficking deficiency could not explain the 75% decrease in inward Na+ current. Interestingly, single channel recordings showed that Nav1.5-L325R exerted a dominant negative effect on the WT channel at the gating level. Both coupled gating and gating probability of WT:L325R dimers were drastically impaired. We conclude that dominant negative suppression exerted by Nav1.5 mutants can also be caused by impairing the WT gating probability, a mechanism resulting from the dimerization and coupled gating of voltage-gated Na+ channel α-subunits. NEW & NOTEWORTHY The presence of dominant negative mutations in the Na+ channel gene leading to Brugada syndrome was supported by our recent findings that Na+ channel α-subunits form dimers. Up until now, the dominant negative effect was thought to be caused by the interaction of the wild-type Na+ channel with trafficking-deficient mutant channels. However, the present study demonstrates that coupled gating of voltage-gated Na+ channels can also be responsible for the dominant negative effect leading to arrhythmias.

Polymorphic variation in the SLC5A7 gene influences infant autonomic reactivity and self-regulation: A neurobiological model for ANS stress responsivity and infant temperament.

OBJECTIVE: To examine the impact of polymorphic variation in the solute carrier family 5 member 7 (SLC5A7) gene on autonomic nervous system (ANS) reactivity indexed by respiratory sinus arrhythmia (RSA) and heart rate (HR) in infants during a dyadic stressor, as well as maternal report of infant self-regulation. Given evidence of race differences in older individuals, race was specifically examined. METHODS: RSA and HR were collected from 111 infants during the still-face paradigm (SFP). Mothers completed the Infant Behavior Questionnaire-Revised short-form. Multi-level mixed effects models examined the impact of SLC5A7 genotype on RSA and HR across the SFP. Linear models tested the influence of genotype on the relation between RSA, HR, and maternal report of infant self-regulation. RESULTS: SLC5A7 genotype significantly predicted RSA stress responsivity (ß = -0.023; p = 0.028) and HR stress responsivity (ß = 0.004; p = 0.002). T-allele carriers exhibited RSA suppression and HR acceleration in response to stress while G/G homozygotes did not suppress RSA and exhibited less HR acceleration. All infants exhibited modest RSA augmentation and HR deceleration during recovery. Race-stratified analyses revealed that White T-allele carriers drove the overall results for both RSA (ß = -0.044; p = 0.007) and HR (ß = 0.006; p = 0.008) with no relation between SLC5A7 genotype and RSA or HR in Black infants. Maternal report of infant orienting/regulation was predicted by the interaction of SLC5A7 genotype and both RSA recovery (ß = 0.359; p = 0.001) and HR recovery (ß = -1.659; p = 0.020). RSA augmentation and HR deceleration during recovery were associated with higher maternal reports of self-regulation among T-allele carriers, a finding again primarily driven by White infants. CONCLUSIONS: Early in development, genetic contributions to ANS are evident and predict maternal report of infant self-regulation within White infants, consistent with prior literature. The lack of associations in Black infants suggest that race differences in physiological reactivity and self-regulation are emerging during the first year of life potentially providing early evidence of disparities in health risk trajectories.

A Systematic Review on the Cost-Effectiveness of Genetic and Electrocardiogram Testing for Long QT Syndrome in Infants and Young Adults.

BACKGROUND: Recent improvements in the identification of the genetic basis of long QT syndrome (LQTS) have led to significant changes in the diagnosis and management of this life-threatening condition. Genetic and electrocardiogram (ECG) tests are the most relevant examples among testing strategies for LQTS, yet their cost-effectiveness remains controversial. OBJECTIVE: The aim of this work was to review the available evidence on the cost-effectiveness of genetic and ECG testing strategies for the diagnosis of LQTS. METHODS: We performed a systematic review of the literature on the cost-effectiveness of genetic and ECG screening strategies for the early detection of LQTS using MEDLINE, EMBASE, and CRD databases between 2000 and 2013. A weighted version of Drummond checklist was instrumental in further assessing the quality of the included studies. RESULTS: We identified four eligible articles. Among them, genetic testing in the early detection of LQTS was cost-effective compared with no testing in symptomatic cases and not cost-effective when compared with watchful waiting in asymptomatic first-degree relatives of patients with established LQTS although it reached cost-effectiveness in higher risk subgroups, whereas ECG testing in neonates was highly cost-effective when compared with any screening strategy. CONCLUSIONS: LQTS profiling and patients' stratification have the potential to improve the disease management. Because of the limited current knowledge in this field, the present review recommends to perform further cost-effectiveness evaluations of the genetic and ECG screening alternatives, especially within European health care systems, which are still not available in the literature on genetic testing.

In silico cardiac risk assessment in patients with long QT syndrome: type 1: clinical predictability of cardiac models.

OBJECTIVES: The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1). BACKGROUND: Although attempts have been made to correlate mutation-specific ion channel dysfunction with patient phenotype in long QT syndrome, these have been largely unsuccessful. Systems-level computational models can be used to predict consequences of complex changes in channel function to the overall heart rhythm. METHODS: A total of 633 LQT1-genotyped subjects with 34 mutations from multinational long QT syndrome registries were studied. Cellular electrophysiology function was determined for the mutations and introduced in a 1-dimensional transmural electrocardiography computer model. The mutation effect on transmural repolarization was determined for each mutation and related to the risk for cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) among patients. RESULTS: Multivariate analysis showed that mutation-specific transmural repolarization prolongation (TRP) was associated with an increased risk for cardiac events (35% per 10-ms increment [p < 0.0001]; ≥upper quartile hazard ratio: 2.80 [p < 0.0001]) and life-threatening events (aborted cardiac arrest/sudden cardiac death: 27% per 10-ms increment [p = 0.03]; ≥upper quartile hazard ratio: 2.24 [p = 0.002]) independently of patients' individual QT interval corrected for heart rate (QTc). Subgroup analysis showed that among patients with mild to moderate QTc duration (<500 ms), the risk associated with TRP was maintained (36% per 10 ms [p < 0.0001]), whereas the patient's individual QTc was not associated with a significant risk increase after adjustment for TRP. CONCLUSIONS: These findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in patients with LQT1, with a more pronounced effect among patients with a lower-range QTc, in whom a patient's individual QTc may provide less incremental prognostic information.

Comparative phenotypic assessment of cardiac pathology, physiology, and gene expression in C3H/HeJ, C57BL/6J, and B6C3F1/J mice.

Human cardiomyopathies often lead to heart failure, a major cause of morbidity and mortality in industrialized nations. Described here is a phenotypic characterization of cardiac function and genome-wide expression from C3H/HeJ, C57BL/6J, and B6C3F1/J male mice. Histopathologic analysis identified a low-grade background cardiomyopathy (murine progressive cardiomyopathy) in eight of nine male C3H/HeJ mice (age nine to ten weeks), but not in male C57BL/6J and in only of ten male B6C3F1/J mice. The C3H/HeJ mouse had an increased heart rate and a shorter RR interval compared to the B6C3F1/J and C57BL/6J mice. Cardiac genomic studies indicated the B6C3F1/J mice exhibited an intermediate gene expression phenotype relative to the 2 parental strains. Disease-centric enrichment analysis indicated a number of cardiomyopathy-associated genes were induced in B6C3F1/J and C3H/HeJ mice, including Myh7, My14, and Lmna and also indicated differential expression of genes associated with metabolic (e.g., Pdk2) and hypoxic stress (e.g. Hif1a). A novel coexpression and integrated pathway network analysis indicated Prkaa2, Pdk2, Rhoj, and Sgcb are likely to play a central role in the pathophysiology of murine progressive cardiomyopathy in C3H/HeJ mice. Our studies indicate that genetically determined baseline differences in cardiac phenotype have the potential to influence the results of cardiotoxicity studies.

Association of A1166C polymorphism in AT(1) receptor gene with baroreflex sensitivity.

The aim of this study was to evaluate the association of A1166C polymorphism in angiotensin II type 1 receptor (AT(1)R) gene with baroreflex sensitivity (BRS in ms/mm Hg; BRSf in mHz/mm Hg) in man. BRS and BRSf were determined by a spectral method in 135 subjects (19-26 years) at a frequency of 0.1 Hz. Genotypes were detected by means of polymerase chain reaction and restriction analysis using enzyme DdeI. We compared BRS and BRSf among genotypes of this polymorphism. The frequency of genotypes of AT(1)R A1166C polymorphism was: 45.9 % (AA, n=62), 45.9 % (AC, n=62), 8.2 % (CC, n=11). Differences in BRS (p<0.05) and BRSf (p<0.01) among genotypes of this single nucleotide polymorphism were found (Kruskal-Wallis: BRS - AA: 7.9+/-3.3, AC: 8.6+/-3.6, CC: 5.9+/-2.3 ms/mm Hg; BRSf - AA: 12.0+/-4.0, AC: 12.0+/-5.0, CC: 8.0+/-3.0 mHz/mm Hg). Compared to carriers of other genotypes (AA+AC) the homozygotes with the less frequent allele (CC) showed significantly lower BRSf (Mann-Whitney: BRSf - AA+AC: 12.0+/-4.0, CC: 8.0+/-3.0 mHz/mm Hg; p<0.01) and borderline lower BRS (BRS - AA+AC: 8.2+/-3.5, CC: 5.9+/-2.5 ms/mm Hg; p=0.07). We found a significant association of A1166C polymorphism in AT(1) receptor gene with baroreflex sensitivity. Homozygosity for the less frequent allele was associated with decreased baroreflex sensitivity.

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making.

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social-emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity.