title: Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology?
abstract: BACKGROUND
  Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ-specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers (PAOs) in atrial tissue has not been previously investigated.
  
  
  RESULTS
  Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAOs using a conformation-specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium-specific marker, the fraction of myocardium colocalizing with PAOs (PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAOs in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAOs in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension.
  
  
  CONCLUSIONS
  PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension.
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Sidorova
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Mace
authors.affiliation: Departments of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN (S.W.).
authors.forename: K Sam
authors.initials: KS
authors.lastname: Wells
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Liudmila V
authors.initials: LV
authors.lastname: Yermalitskaya
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN (P.F.S., Y.S.).
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Su
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN (P.F.S., Y.S.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Departments of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN (J.B.A., A.B.F.).
authors.forename: James B
authors.initials: JB
authors.lastname: Atkinson
authors.affiliation: Departments of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN (J.B.A., A.B.F.).
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Prinsen
authors.affiliation: Department of Cardiac Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.G.B., M.R.P., J.P.G., S.J.H., S.K.B.).
authors.forename: John G
authors.initials: JG
authors.lastname: Byrne
authors.affiliation: Department of Cardiac Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.G.B., M.R.P., J.P.G., S.J.H., S.K.B.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Petracek
authors.affiliation: Department of Cardiac Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.G.B., M.R.P., J.P.G., S.J.H., S.K.B.).
authors.forename: James P
authors.initials: JP
authors.lastname: Greelish
authors.affiliation: Department of Cardiac Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.G.B., M.R.P., J.P.G., S.J.H., S.K.B.).
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Hoff
authors.affiliation: Department of Cardiac Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.G.B., M.R.P., J.P.G., S.J.H., S.K.B.).
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Ball
authors.affiliation: University of California, IrvineCA (C.G.G.).
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.affiliation: Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (T.N.S., L.C.M., L.V.Y., J.K.P., N.J.B., J.V.B., K.T.M.).
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Murray
mesh_terms: D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000032:analysis*; D016275:Atrial Function; D009320:Atrial Natriuretic Factor / Q000032:analysis; D005260:Female; D005355:Fibrosis; D006325:Heart Atria / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011228:Prealbumin / Q000032:analysis; D066329:Protein Aggregates; D016032:Randomized Controlled Trials as Topic
chemical_list: D016564:Amyloid beta-Protein Precursor; D011228:Prealbumin; D066329:Protein Aggregates; D009320:Atrial Natriuretic Factor
keywords: amyloid; atrial natriuretic peptide; atrium; preamyloid oligomers