title: Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosterone system inhibitors in an aged mouse model.
abstract: Myocardial fibrosis increases arrhythmia vulnerability of the diseased heart. The renin-angiotensin-aldosterone system (RAAS) governs myocardial collagen synthesis. We hypothesized that reducing cardiac fibrosis by chronic RAAS inhibition would result in reduced arrhythmia vulnerability of the senescent mouse heart. Wild-type mice (52 wk old) were treated for 36 wk: 1) untreated control (C); 2) eplerenone (E); 3) losartan (L); and 4) cotreatment with eplerenone and losartan (EL). Ventricular epicardial activation mapping was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by one to three premature stimuli and burst pacing. Longitudinal and transverse conduction velocity and dispersion of conduction were determined during pacing at a basic cycle length of 150 ms. Sirius red staining (collagen) was performed. As a result, in the RV of mice in the E, L, and EL groups, transverse conduction velocity was significantly increased and anisotropic ratio was significantly decreased compared with those values of mice in the C group. Anisotropic reentrant arrhythmias were induced in 52% of untreated mice and significantly reduced to 22%, 26%, and 16% in the E, L, and EL groups, respectively. Interstitial fibrosis was significantly decreased in both the RV and LV of all treated groups. Scattered patches of replacement fibrosis were found in 90% of untreated hearts, which were significantly reduced in the E, L, and EL groups. A strong correlation between the abundance of patchy fibrosis and arrhythmia inducibility was found. In conclusion, chronic RAAS inhibition limited aging-related interstitial fibrosis. The lower arrhythmogeneity of treated mice was directly correlated to the reduced amount of patchy fibrosis.
authors.affiliation: Div. of Heart & Lungs, Dept. of Medical, Physiology, Univ. Medical Ctr. Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands.
authors.forename: Mera
authors.initials: M
authors.lastname: Stein
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boulaksil
authors.forename: John A
authors.initials: JA
authors.lastname: Jansen
authors.forename: Eva
authors.initials: E
authors.lastname: Herold
authors.forename: Maartje
authors.initials: M
authors.lastname: Noorman
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Marien J C
authors.initials: MJ
authors.lastname: Houtman
authors.forename: Markus A
authors.initials: MA
authors.lastname: Engelen
authors.forename: Richard N W
authors.initials: RN
authors.lastname: Hauer
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
mesh_terms: D000367:Age Factors; D000375:Aging; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D002450:Cell Communication / Q000187:drug effects; D016922:Cellular Senescence; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D056149:Epicardial Mapping; D000077545:Eplerenone; D005260:Female; D005355:Fibrosis; D006329:Heart Conduction System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006331:Heart Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018031:Connexin 43; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone; D019808:Losartan