β-Blocker Therapy and Heart Rate Control During Exercise Testing in the General Population: Role of a Common G-Protein β-3 Subunit Variant

• Lee TH : Eulogy for a quality measure.N. Engl. J. Med.357(12) , 1175–1177 (2007).
   PubMed Web of Science ®Google Scholar
• Gullestad L , WikstrandJ, DeedwaniaP et al.: What resting heart rate should one aim for when treating patients with heart failure with a β-blocker? experiences from the metoprolol controlled release/extended release randomized intervention trial in chronic heart failure (MERIT-HF).J. Am. Coll. Cardiol.45(2) , 252–259 (2005).
   PubMed Web of Science ®Google Scholar
• Kjekshus JK : Importance of heart rate in determining β-blocker efficacy in acute and long-term acute myocardial infarction intervention trials.Am. J. Cardiol.57(12) , 43–49 (1986).
   PubMed Web of Science ®Google Scholar
• Fox K , BorerJS, CammAJ et al.: Resting heart rate in cardiovascular disease.J. Am. Coll. Cardiol.50(9) , 823–830 (2007).
   PubMed Web of Science ®Google Scholar
• Wikstrand J , HjalmarsonA, WaagsteinF et al.: Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF).J. Am. Coll. Cardiol.40(3) , 491–498 (2002).
   PubMed Web of Science ®Google Scholar
• Messerli FH , BangaloreS, JuliusS: Risk/benefit assessment of β-blockers and diuretics precludes their use for first-line therapy in hypertension.Circulation117(20) , 2706–2715 (2008).
   PubMed Web of Science ®Google Scholar
• Cutler JA , DavisBR: Thiazide-type diuretics and β-adrenergic blockers as first-line drug treatments for hypertension.Circulation117(20) , 2691–2704 (2008).
   PubMed Web of Science ®Google Scholar
• Gislason GH , RasmussenJN, AbildstromSZ et al.: Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes.Circulation116(7) , 737–744 (2007).
   PubMed Web of Science ®Google Scholar
• Devereaux PJ , YangH, YusufS et al.: Effects of extended-release metoprolol succinate in patients undergoing non cardiac surgery (POISE trial): a randomised controlled trial.Lancet371(9627) , 1839–1847 (2008).
   PubMed Web of Science ®Google Scholar
• Ingelsson E , LarsonMG, VasanRS et al.: Heritability, linkage, and genetic associations of exercise treadmill test responses.Circulation115(23) , 2917–2924 (2007).
   PubMed Web of Science ®Google Scholar
• Wettschureck N , OffermannsS: Mammalian G proteins and their cell type specific functions.Physiol. Rev.85(4) , 1159–1204 (2005).
   PubMed Web of Science ®Google Scholar
• Siffert W , RosskopfD, SiffertG et al.: Association of a human G-protein β3 subunit variant with hypertension.Nat. Genet.18(1) , 45–48 (1998).
   PubMed Web of Science ®Google Scholar
• Rosskopf D , SchürksM, RimmbachC, SchafersR: Genetics of arterial hypertension and hypotension.Naunyn Schmiedebergs Arch. Pharmacol.374(5–6) , 429–469 (2007).
   PubMed Web of Science ®Google Scholar
• Nürnberger J , DammerS, MitchellA et al.: Effect of the C825T polymorphism of the G protein β 3 subunit on the systolic blood pressure-lowering effect of clonidine in young, healthy male subjects.Clin. Pharmacol. Ther.74(1) , 53–60 (2003).
   PubMed Web of Science ®Google Scholar
• Siffert W : G protein polymorphisms in hypertension, atherosclerosis, and diabetes.Annu. Rev. Med.56 , 17–28 (2005).
   PubMed Web of Science ®Google Scholar
• Baumgart D , NaberC, HaudeM et al.: G protein β3 subunit 825T allele and enhanced coronary vasoconstriction on α(2)-adrenoceptor activation.Circ. Res.85(10) , 965–969 (1999).
   PubMed Web of Science ®Google Scholar
• Schäfers RF , NürnbergerJ, RutzA et al.: Haemodynamic characterization of young normotensive men carrying the 825T-allele of the G-protein β3 subunit.Pharmacogenetics11(6) , 461–470 (2001).
   PubMedGoogle Scholar
• Kurnik D , FriedmanEA, MuszkatM et al.: Genetic variants in the α2C-adrenoceptor and G-protein contribute to ethnic differences in cardiovascular stress responses.Pharmacogenet. Genomics18 , 743–750 (2008).
   PubMed Web of Science ®Google Scholar
• Filigheddu F , ReidJE, TroffaC et al.: Genetic polymorphisms of the β-adrenergic system: association with essential hypertension and response to β-blockade.Pharmacogenomics J.4(3) , 154–160 (2004).
   PubMed Web of Science ®Google Scholar
• Matsunaga T , NagasumiK, YamamuraT et al.: Association of C825T polymorphism of G protein β3 subunit with the autonomic nervous system in young healthy Japanese individuals.Am. J. Hypertens.18(4 Pt 1) , 523–529 (2005).
   PubMed Web of Science ®Google Scholar
• Völzke H , AlteD, SchmidtCO et al.: Cohort profile: the study of health in Pomerania.Int. J. Epidemiol. (2010) (Epub ahead of print).
   PubMedGoogle Scholar
• Lang RM , BierigM, DevereuxRB et al.: Recommendations for chamber quantification.Eur. J. Echocardiogr.7(2) , 79–108 (2006).
   PubMed Web of Science ®Google Scholar
• Baecke JA , BuremaJ, FrijtersJE: A short questionnaire for the measurement of habitual physical activity in epidemiological studies.Am. J. Clin. Nutr.36(5) , 936–942 (1982).
   PubMed Web of Science ®Google Scholar
• Schürks M , KurthT, StudeP et al.: G protein β3 polymorphism and triptan response in cluster headache.Clin. Pharmacol. Ther.82(4) , 396–401 (2007).
   PubMed Web of Science ®Google Scholar
• Tobler AR , ShortS, AndersenMR et al.: The SNPlex genotyping system: a flexible and scalable platform for SNP genotyping.J. Biomol. Tech.16(4) , 398–406 (2005).
   PubMedGoogle Scholar
• Rosskopf D , MantheyI, HabichC et al.: Identification and characterization of G β 3s2, a novel splice variant of the G-protein β 3 subunit.Biochem. J.371(Pt 1) , 223–232 (2003).
   PubMed Web of Science ®Google Scholar
• Jones N : Clinical Exercise Testing (3rd Edition). WB Saunders Co., PA, USA, 152–155 (1988).
   Google Scholar
• Savonen KP , LakkaTA, LaukkanenJA et al.: Heart rate response during exercise test and cardiovascular mortality in middle-aged men.Eur. Heart J.27(5) , 582–588 (2006).
   PubMed Web of Science ®Google Scholar
• Wasserman K , HansenJE, SueDY, StringerWW, WhippBJ: Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications (4th Edition). Lippincott, Williams and Wilkins, PA, USA (2004).
   Google Scholar
• Astrand I : Aerobic work capacity in men and women with special reference to age.Acta Physiol. Scand Suppl.49(169) , 1–92 (1960).
   PubMedGoogle Scholar
• Khan MN , PothierCE, LauerMS: Chronotropic incompetence as a predictor of death among patients with normal electrograms taking b blockers (metoprolol or atenolol).Am. J. Cardiol.96(9) , 1328–1333 (2005).
   PubMed Web of Science ®Google Scholar
• Lauer MS , FrancisGS, OkinPM, PashkowFJ, SnaderCE, MarwickTH: Impaired chronotropic response to exercise stress testing as a predictor of mortality.JAMA281(6) , 524–529 (1999).
   PubMed Web of Science ®Google Scholar
• Robergs RA , LandwehrA: The surprising history of the ‘HRmax=220-age‘ equation.J. Exercise Physiol.5(2) , 1–8 (2002).
   Google Scholar
• Inbar O , OrenA, ScheinowitzM, RotsteinA, DlinR, CasaburiR: Normal cardiopulmonary responses during incremental exercise in 20- to 70-yr-old men.Med. Sci. Sports Exerc.26(5) , 538–546 (1994).
   PubMed Web of Science ®Google Scholar
• Rosskopf D , MantheyI, SiffertW: Identification and ethnic distribution of major haplotypes in the gene GNB3 encoding the G-protein β3 subunit.Pharmacogenetics12(3) , 209–220 (2002).
   PubMedGoogle Scholar
• Wenzel RR , SiffertW, BruckH, PhilippT, SchafersRF: Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation.Pharmacogenetics12(6) , 489–495 (2002).
   PubMedGoogle Scholar
• Mitchell A , LuckebergfeldB, BuhrmannS et al.: Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism.Clin. Pharmacol. Ther.76(5) , 396–408 (2004).
   PubMed Web of Science ®Google Scholar
• Meirhaeghe A , BautersC, HelbecqueN et al.: The human G-protein β3 subunit C825T polymorphism is associated with coronary artery vasoconstriction.Eur. Heart J.22(10) , 845–848 (2001).
   PubMed Web of Science ®Google Scholar
• Mitchell A , PaceM, NurnbergerJ et al.: Insulin-mediated venodilation is impaired in young, healthy carriers of the 825T allele of the G-protein β3 subunit gene (GNB3).Clin. Pharmacol. Ther.77(6) , 495–502 (2005).
   PubMed Web of Science ®Google Scholar
• Bagos PG , ElefsiniotiAL, NikolopoulosGK, HamodrakasSJ: The GNB3 C825T polymorphism and essential hypertension: a meta-analysis of 34 studies including 14,094 cases and 17,760 controls.J. Hypertens.25(3) , 487–500 (2007).
   PubMed Web of Science ®Google Scholar
• Sartori M , SempliciniA, SiffertW et al.: G-protein β3-subunit gene 825T allele and hypertension: a longitudinal study in young grade I hypertensives.Hypertension42(5) , 909–914 (2003).
   PubMed Web of Science ®Google Scholar
• Rankinen T , RiceT, LeonAS et al.: G protein β 3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study.Physiol. Genomics8(2) , 151–157 (2002).
   PubMed Web of Science ®Google Scholar
• Wilkie MJ , SmithD, ReidIC et al.: A splice site polymorphism in the G-protein b subunit influences antidepressant efficacy in depression.Pharmacogenet. Genomics17(3) , 207–215 (2007).
   PubMed Web of Science ®Google Scholar
• Wang T , PlumptonC, BrownMJ: Selective β1-adrenoceptor blockade enhances the activity of the stimulatory G-protein in human atrial myocardium.Br. J. Pharmacol.128(1) , 135–141 (1999).
   PubMed Web of Science ®Google Scholar
• Rosskopf D , MichelMC: Pharmacogenomics of G protein-coupled receptor ligands in cardiovascular medicine.Pharmacol. Rev.60(4) , 513–535 (2008).
   PubMed Web of Science ®Google Scholar
• Rochais F , VilardagaJP, NikolaevVO, BunemannM, LohseMJ, EngelhardtS: Real-time optical recording of β1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol.J. Clin. Invest.117(1) , 229–235 (2007).
   PubMed Web of Science ®Google Scholar
• Lauer MS , OkinPM, LarsonMG, EvansJC, LevyD: Impaired heart rate response to graded exercise. Prognostic implications of chronotropic incompetence in the Framingham heart study.Circulation93(8) , 1520–1526 (1996).
   PubMed Web of Science ®Google Scholar

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• ATC Index with DDDs and the Guidelines for ATC classification and DDD assignment. WHO Collaborating Centre for Drug Statistics Methodology: Oslo, Norway www.whocc.no/atcddd
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