Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension.
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.
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
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