title: Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension.
abstract: We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180+/-3 mm Hg) compared with dTGRs (208+/-5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110+/-3 and 119+/-6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT(c) intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.
authors.affiliation: Medical Faculty of the Charité, Experimental and Clinical Research Center, Franz Volhard Clinic and HELIOS Klinikum Berlin-Buch, Berlin, Germany. robert.fischer@charite.de
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Marija
authors.initials: M
authors.lastname: Markovic
authors.forename: Sandra
authors.initials: S
authors.lastname: Feldt
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Andrej
authors.initials: A
authors.lastname: Gapelyuk
authors.forename: Ines
authors.initials: I
authors.lastname: Schwarz
authors.forename: Udo B
authors.initials: UB
authors.lastname: Zacharzowsky
authors.forename: Ralph
authors.initials: R
authors.lastname: Plehm
authors.forename: Erdal
authors.initials: E
authors.lastname: Safak
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.forename: Alexander
authors.initials: A
authors.lastname: Schirdewan
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
mesh_terms: D000577:Amides / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology; D001794:Blood Pressure / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D006332:Cardiomegaly / Q000209:etiology; D018031:Connexin 43 / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D004594:Electrophysiology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005650:Fumarates / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D053798:Magnetocardiography; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000808:Angiotensinogen; D000959:Antihypertensive Agents; D018031:Connexin 43; D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D005650:Fumarates; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren