title: Beta2-adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension.
abstract: OBJECTIVE
  Although blood pressure is considered the major determinant of left ventricular hypertrophy in hypertension, genetic variability is increasingly being considered among the factors influencing this complication. beta(2)-Adrenergic receptors (beta(2)ARs) are up-regulated in hypertension and largely polymorphic within the human population. Recently, we have shown that the Glu27 beta(2)AR variant is strongly associated with cardiac hypertrophy in hypertension. The objective of this study is to verify whether this polymorphism also affects hypertrophy regression in response to antihypertensive therapy.
  
  
  METHODS
  In a prospective follow-up study we screened 970 hypertensive patients of Caucasian descent for the Gly16Arg, Gln27Glu, and Thr164Ile beta(2)AR polymorphisms and left ventricular echocardiographic hypertrophy and assigned selected patients to enalapril or atenolol to assess left ventricular hypertrophy regression after 2-year follow-up. Results were stratified according to treatment and the Glu27Gln polymorphism of the beta(2)AR. In cells with stable overexpression of the Glu27 or Gln27 variant of beta(2)AR, we also explored the implications of this polymorphism on hypertrophy-related intracellular signal transduction.
  
  
  RESULTS
  Among hypertensive patients, the Gly16 allele was found in 63% of patients and the Glu27 allele was found in 40.6%. Both polymorphisms were in linkage disequilibrium, as expected. Four hundred forty-one hypertrophic hypertensive patients completed the 2-year follow-up. At baseline, patients carrying at least 1 allele of the Glu27 variant presented with a larger cardiac size despite similar blood pressure levels (142.9 +/- 22.5 g/m(2) in Glu27 carriers versus 138.2 +/- 18.4 g/m(2) in Gln27 carriers, P < .02). Blood pressure normalization was achieved by both drugs. At follow-up, compared with the Gln27 patients, the Glu27 patients showed a larger reduction in hypertrophy when treated with enalapril (percent change in left ventricular mass, -6.3% +/- 7.7% in Glu27 carriers versus -2.18% +/- 7.9% in Gln27 carriers; P < .05) but not with atenolol therapy (-2.8% +/- 8.9% in Glu27 carriers versus -2.4% +/- 8.8% in Gln27 carriers, P = not significant). In in vitro studies the activation of p38 and extracellular signal-regulated kinase (ERK-) 1/2 (data not shown) and the activity of the atrial natriuretic factor (ANF) promoter after isoproterenol (INN, isoprenaline) stimulation were larger in Glu27 beta(2)AR overexpressing cells than in Gln27 beta(2)AR overexpressing cells (fold difference compared with unstimulated cells, 9.7 +/- 2.9 for Glu27 beta(2)AR versus 4.2 +/- 0.3 for Gln27 beta(2)AR; P < .05).
  
  
  CONCLUSIONS
  The Glu27 variant of beta(2)AR enhances hypertension-induced left ventricular hypertrophy. In these patients angiotensin-converting enzyme inhibitors are more efficient than beta-blockers in reducing cardiac size.
authors.affiliation: Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II di Napoli, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Raffaele
authors.initials: R
authors.lastname: Izzo
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.forename: Francesca
authors.initials: F
authors.lastname: Lanni
authors.forename: Daniela
authors.initials: D
authors.lastname: Sorriento
authors.forename: Gianni Luigi
authors.initials: GL
authors.lastname: Iovino
authors.forename: Francesco
authors.initials: F
authors.lastname: Rozza
authors.forename: Nicola
authors.initials: N
authors.lastname: De Luca
authors.forename: Ornella
authors.initials: O
authors.lastname: Priante
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use; D001262:Atenolol / Q000627:therapeutic use; D004656:Enalapril / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D018343:Receptors, Adrenergic, beta-2; D001262:Atenolol; D004656:Enalapril