Beta1-adrenergic receptor polymorphisms and clinical efficacy of betaxolol hydrochloride in normal volunteers.

OBJECTIVE: To evaluate the relationship between polymorphisms in the gene encoding the beta1-adrenergic receptor (beta1-AR) and clinical response to betaxolol hydrochloride 0.25% in a small pilot study of normal volunteers. DESIGN: Prospective nonrandomized comparative trial. PARTICIPANTS: Forty-eight consecutive normal volunteers who met all eligibility requirements for inclusion into this study. METHODS: Baseline intraocular pressure (IOP) was recorded. Subjects began treatment with betaxolol (1 drop both eyes twice daily) and underwent follow-up IOP recordings at 3 and 6 weeks. Peripheral blood was obtained for genetic analysis. MAIN OUTCOME MEASURES: Response to betaxolol was calculated as the change in mean IOP from baseline (averaged between both eyes and averaged between both follow-up visits). The beta1-AR genotype was determined by polymerase chain reaction with restriction fragment length polymorphisms at codons 49 (serine [Ser] or glycine [Gly]) and 389 (arginine [Arg] or Gly). RESULTS: There were 32 Ser49 homozygotes and 16 Gly49 carriers. There were no statistically significant differences between the Ser49 homozygotes and the Gly49 carriers with respect to baseline IOP or response to betaxolol therapy. There were 25 Arg389 homozygotes and 23 Gly389 carriers (22 heterozygotes and 1 Gly389 homozygote). As compared with Gly389 carriers, the Arg389 homozygotes had a higher baseline IOP (15.8 mmHg vs. 13.7 mmHg; P = 0.009) and a greater magnitude of response to betaxolol therapy (-3.4 mmHg vs. -1.5 mmHg; P = 0.0009). The Ser49 homozygote genotype was not independently associated with baseline IOP (P = 0.47) or with a response to betaxolol (P = 0.99). The Arg389 homozygote genotype was independently associated with a higher baseline IOP (P = 0.03) and a greater response to betaxolol (P = 0.03), even after adjusting for baseline IOP. CONCLUSIONS: In this small pilot series, a single nucleotide polymorphism at codon 389 in the beta1-AR seems to correlate with a response to betaxolol therapy in normal, nonglaucomatous volunteers. There was no such correlation at codon 49. The polymorphism at codon 389 may predict short-term response to betaxolol and may serve as a determinant of response to betaxolol and other adrenergic agents in glaucomatous eyes requiring treatment.

Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol.

OBJECTIVES: Marked interpatient variability exists in blood pressure response to beta-blocker monotherapy. We tested the hypothesis that 2 common polymorphisms in the gene for beta(1)-adrenergic receptor are associated with antihypertensive response to metoprolol in patients with uncomplicated hypertension. METHODS: Forty hypertensive men and women aged 35 to 65 years were studied. Baseline studies included 24-hour ambulatory blood pressure monitoring. Patients took 50 mg metoprolol twice daily with weekly titration to response or 200 mg twice daily. After a minimum of 4 weeks at stable dose, treatment phase 24-hour ambulatory blood pressure monitoring was repeated. The codon 49 and 389 genotypes for beta(1)-adrenergic receptor were determined by polymerase chain reaction with restriction fragment length polymorphism. Multilinear regression was performed to determine the impact of genotype and other variables on blood pressure response to metoprolol. RESULTS: Patients homozygous for Arg at codon 389 had a nearly 3-fold greater reduction in daytime diastolic blood pressure (-13.3% +/- 8.4% versus -4.5% +/- 8.2%, P =.0018) compared with those who carried the variant allele. The haplotype pair (diplotype) for beta(1)-adrenergic receptor was also a significant predictor of response, with patients having the Ser49Arg389/Ser49Arg389 diplotype demonstrating a decline in blood pressure of 14.7 mm Hg versus 0.5 mm Hg in patients with the Gly49Arg389/Ser49Gly389 diplotype. In multiregression analysis, baseline daytime diastolic blood pressure, codon 389 genotype, and codon 49 genotype were significant predictors of blood pressure after treatment. CONCLUSIONS: Our data suggest that beta(1)-adrenergic receptor polymorphisms are important determinants of antihypertensive response to metoprolol. In the future, codon 49 and 389 genotypes or beta(1)-adrenergic receptor haplotypes might be used to predict the diastolic blood pressure response to metoprolol in patients with hypertension.

Estimating the impact of off-balancing forces upon cardiopulmonary resuscitation during ambulance transport.

INTRODUCTION: Survival from out-of-hospital cardiac arrest (OOH-CA) remains poor, especially when patients are transported with CPR in progress. Previous investigations suggest that CPR quality erodes during transport due to the austere environment. We sought to determine how frequently ambulance personnel are exposed to off-balancing forces during transport of OOH-CA patients and to estimate the potential impact on CPR and coronary perfusion pressure (CPP). METHODS: An onboard monitoring system was utilized to record acceleration data during the transport of 50 OOH-CA patients. Acceleration vectors were calculated for every second of drive time (speed >0 m/s). A model was constructed to estimate the potential impact of these vectors upon CPR and CPP. These data were then compared to a case-control cohort of 102 matched non-urgent transports. RESULTS: A total of 5.8h of drive time was analyzed in the cardiac arrest cohort. Mean transport time was 8 min 53 s with a mean drive time of 6 min 58 s. Critical acceleration threshold was exceeded 60% of transport time (202.42 min, mean 4.05 min/transport) yielding a potential hands-off ratio of 0.42 with a CPP<15 mmHg 62% of drive time. Ambulance speed was inversely related to the magnitude of off-balancing forces. Comparison to 14.1h of control cohort yielded similar off-balancing forces and relationships despite lower speeds and no "lights and siren" use. CONCLUSION: Critical acceleration forces occur frequently during transport of OOH-CA patients and may directly effect CPR quality and thereby CPP. These force vectors are stronger and more frequent at slower speeds, comprising the majority of ambulance drive time. Reducing speed or transporting OOH-CA patients without lights and sirens does little to mitigate these forces.