title: Coordinate changes in Myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype.
abstract: BACKGROUND
  The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying.
  
  
  METHODS
  One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction.
  
  
  RESULTS
  Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide.
  
  
  CONCLUSIONS
  We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.
authors.affiliation: Division of Cardiology, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Abraham
authors.forename: E M
authors.initials: EM
authors.lastname: Gilbert
authors.forename: B D
authors.initials: BD
authors.lastname: Lowes
authors.forename: W A
authors.initials: WA
authors.lastname: Minobe
authors.forename: P
authors.initials: P
authors.lastname: Larrabee
authors.forename: R L
authors.initials: RL
authors.lastname: Roden
authors.forename: D
authors.initials: D
authors.lastname: Dutcher
authors.forename: J
authors.initials: J
authors.lastname: Sederberg
authors.forename: J A
authors.initials: JA
authors.lastname: Lindenfeld
authors.forename: E E
authors.initials: EE
authors.lastname: Wolfel
authors.forename: S F
authors.initials: SF
authors.lastname: Shakar
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: K
authors.initials: K
authors.lastname: Volkman
authors.forename: J V
authors.initials: JV
authors.lastname: Linseman
authors.forename: R A
authors.initials: RA
authors.lastname: Quaife
authors.forename: A D
authors.initials: AD
authors.lastname: Robertson
authors.forename: M R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology*; D000077261:Carvedilol; D002395:Catecholamines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype; D011412:Propanolamines / Q000627:therapeutic use; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D011877:Radionuclide Imaging; D011943:Receptors, Adrenergic, beta / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D016277:Ventricular Function, Left
chemical_list: D000959:Antihypertensive Agents; D002227:Carbazoles; D002395:Catecholamines; D011412:Propanolamines; D020033:Protein Isoforms; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D008790:Metoprolol