β2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death
ABSTRACT Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk.
In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study.
Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
- SourceAvailable from: Maryl R Johnson[Show abstract] [Hide abstract]
ABSTRACT: Insulin resistance is prevalent in heart failure (HF) patients, and beta2 adrenergic receptors (beta2-AR) are involved in glucose homeostasis. We hypothesized that beta2-AR Gln27Glu and Arg16Gly polymorphisms affect insulin resistance in HF patients, and we explored if effects of beta2-AR polymorphisms on glucose handling are modified by choice of beta blocker. We studied 30 nondiabetic adults with HF and a history of systolic dysfunction; 15 were receiving metoprolol succinate, and 15 were receiving carvedilol. We measured fasting glucose, insulin, and insulin resistance, and we determined beta2-AR genotypes at codons 27 and 16. The cohort was insulin resistant with a mean HOMA-IR score of 3.4 (95% CI, 2.3 to 4.5; normal value, 1.0). Patients with the Glu27Glu genotype exhibited higher insulin and HOMA-IR compared to individuals carrying a Gln allele (P = 0.019). Patients taking carvedilol demonstrated lower insulin resistance if also carrying a wild-type allele at codon 27 (fasting insulin, 9.8 +/- 10.5 versus 20.5 +/- 2.1 for variant, P = 0.072; HOMA-IR, 2.4 +/- 2.7 versus 5.1 +/- 0.6, P = 0.074); those on metoprolol succinate had high insulin resistance irrespective of genotype. The beta2-AR Glu27Glu genotype may be associated with higher insulin concentrations and insulin resistance in patients with HF. Future studies are needed to confirm whether treatment with carvedilol may be associated with decreased insulin and insulin resistance in beta2-AR codon 27 Gln carriers.Journal of cardiovascular pharmacology 12/2008; 52(6):500-6. DOI:10.1097/FJC.0b013e31818f5739 · 2.11 Impact Factor
Article: GENÈTICA I CAOS ELÈCTRIC
Conference Paper: Mechanical reliability improvement with proper package design in CSP[Show abstract] [Hide abstract]
ABSTRACT: For a growing development and design of high performance ICs, more and more functions are demand to be contained in a Chip Scale Package (CSP) for the application that requires low profiles and small footprints. For a communication device and portable electronic products, such as cellular phone and PDA, the printed circuit board (PCB) and device bear a low frequency vibration by a random pressing. The CSP is used in these products. Besides the package level reliability importance to development, the board level reliability is also critical. Mostly board level reliability is tested under temperature cycling and other thermal stress tests, but the request for a mechanical stress test of CSP after mounting has increased recently. With thinner package profile requirement in CSP, a thinner substrate is necessary. More reliability issues arise with a thinner substrate to provide the mechanical support. Due to the different kinds of design layout of the substrate, they induce different stress distributions which affect the IC chip directly during various assembly processes. Therefore, proper substrate layout design does not only achieve the thermally and electrically functional requirements, but also prevents critical mechanical problems. For comparison and confirmation of the phenomena, Moire interferometry was employed along with finite element analysis. The purpose of this paper is also to investigate the board level reliability with different solder ball pad opening diameters in the substrate and solder ball diameters for a bending cyclic test. It includes the bending cyclic and bending limit tests. Further, to modify the solder ball size and composition with eutectic and lead free solder/paste is discussed in this paper.Electronic Materials and Packaging, 2002. Proceedings of the 4th International Symposium on; 01/2003