title: Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload.
abstract: OBJECTIVE
  Women with aortic stenosis develop a more concentric form of LV hypertrophy than men. However, the molecular factors underlying sex differences in LV remodelling are incompletely understood. We took an unbiased approach to identify sex-specific patterns in gene expression and pathway regulation, and confirmed the most prominent findings in human hearts.
  
  
  RESULTS
  Echocardiography was performed in 104 patients (53.8% women) with aortic stenosis before aortic valve replacement. LV mass, LV end-diastolic diameter, and relative wall thickness were included in a factor analysis to generate an index classifying LV remodelling as adaptive or maladaptive. Maladaptive remodelling was present in 64.6% of male and in 32.7% of female patients (P < 0.01). Genome-wide expression profiling of LV samples was performed in a representative subgroup of 19 patients (52.6% women) compared with samples from healthy controls (n = 18). Transcriptome characterization revealed that fibrosis-related genes/pathways were induced in male overloaded ventricles, while extracellular matrix-related and inflammatory genes/pathways were repressed in female overloaded ventricles (adjusted P < 0.05). We confirmed gene regulation by quantitative real-time reverse transcription-polymerase chain reaction and immunoblotting analysis, and we further demonstrate the relevance of our findings by histological documentation of higher fibrosis in men than in women.
  
  
  CONCLUSIONS
  We conclude that in pressure overload distinct molecular processes are regulated between men and women. Maladaptive LV remodelling occurs more frequently in men and is associated with greater activation of profibrotic and inflammatory markers. Collectively, sex-specific regulation of these processes may contribute to sex differences in the progression to heart failure.
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin site, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.forename: Elke
authors.initials: E
authors.lastname: Dworatzek
authors.forename: George
authors.initials: G
authors.lastname: Petrov
authors.forename: Holger
authors.initials: H
authors.lastname: Summer
authors.forename: Tabea Marie
authors.initials: TM
authors.lastname: Schulze
authors.forename: Istvan
authors.initials: I
authors.lastname: Baczko
authors.forename: Christoph
authors.initials: C
authors.lastname: Knosalla
authors.forename: Stefan
authors.initials: S
authors.lastname: Golz
authors.forename: Roland
authors.initials: R
authors.lastname: Hetzer
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D001706:Biopsy; D004452:Echocardiography; D005260:Female; D005355:Fibrosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D015151:Immunoblotting; D007249:Inflammation / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D008297:Male; D012313:RNA / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D012737:Sex Factors; D046888:Tissue Array Analysis; D059467:Transcriptome / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D012313:RNA
keywords: Gene expression; Hypertrophy; Pressure overload; Sex differences; Transcriptomics