This article is available online at http://www.jlr.org Cytochrome P450 (CYP) enzymes catalyze the formation of biologically active epoxy-and hydroxy-metabolites of long-chain PUFAs ( 1 ). Traditionally, and in line with the prevalence of n-6 PUFAs in the "Western diet", arachidonic acid (AA) (20:4 n-6) has been considered as the main precursor and the corresponding metabolites were categorized as a subclass of eicosanoids ( 2 ). CYP-eicosanoid formation is also known as the "third branch of the AA cascade," complementary to the previously discovered cyclooxygenase (COX)-and lipoxygenase (LOX)-initiated pathways of prostanoid and leukotriene formation ( 3, 4 ).Physiologically important AA-derived CYP-eicosanoids include a set of regio-and stereoisomeric epoxyeicosatrienoic acids (EETs) and 20-HETE ( 2, 5 ). EETs and 20-HETE play partially opposing roles in the regulation of vascular, renal, and cardiac function ( 6-9 ). The contribution of EETs to cardiovascular function is infl uenced by the soluble epoxide hydrolase (sEH) that metabolizes EETs to less potent dihydroxyeicosatrienoic acids (DHETs) ( 10 ). Imbalances in CYP-eicosanoid formation are linked to the development of endothelial dysfunction and hypertension; ischemia-induced injury of the heart, kidney and brain; infl ammatory disorders; and atherosclerosis (11)(12)(13)(14)(15)(16)(17).Recent studies demonstrated that the same CYP isoforms that epoxidize or hydroxylate AA, also effi ciently metabolize

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 (180Ϯ3 mm Hg) compared with dTGRs (208Ϯ5 mm Hg). Aliskiren-treated dTGRs and SpragueDawley rats were normotensive (110Ϯ3 and 119Ϯ6 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. Key Words: angiotensin II Ⅲ renin inhibition Ⅲ n-3 PUFA Ⅲ arrhythmias Ⅲ magnetocardiography H ypertensive heart disease causes heart failure and arrhythmia propensity. Ischemia, cardiac hypertrophy, fibrosis, inflammation, and electrical remodeling all contribute to the pathogenesis. 1,2 The renin-angiotensin-aldosterone system is a primary driver, and its blockade is state-of-the-art therapy. We provided initial evidence that direct renin inhibition (DRI) in transgenic rats harboring the human renin and angiotensinogen genes (dTGRs) improves target organ damage. 3-5 Untreated dTGRs developed severe hypertension, hypertrophy, inflammation, fibrosis, and small myocardial infarctions. Ventricular arrhythmias and, consequently, sudden cardiac death contributed to the high mortality rate at the early age of 7 weeks. 6 Electrical remodeling in dTGRs included dysregulation of the I to potassium channel, Ca 2ϩ -cycling proteins, and connexin (Cx) 43 gap junctions. 6,7 n-3 polyunsaturated fatty acids (PUFAs), contained in marine fish oil, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lead to cardioprotection and reduce sudden cardiac death. 8 The molecular mechanisms by which n-3 PUFAs exert their cardioprotective effects are not fully understood. n-3 PUFAs putatively affect membran...

Rats harboring the human renin and angiotensinogen genes (dTGR) feature angiotensin (ANG) II/ hypertension-induced cardiac damage and die suddenly between wk 7 and 8. We observed by electrocardiogram (ECG) telemetry that ventricular tachycardia (VT) is a common terminal event in these animals. Our aim was to investigate electrical remodeling. We used ECG telemetry, noninvasive cardiac magnetic field mapping (CMFM) at wk 5 and 7, and performed in vivo programmed electrical stimulation at wk 7. We also investigated whether or not losartan (Los; 30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) would prevent electrical remodeling. Cardiac hypertrophy and systolic blood pressure progressively increased in dTGR compared with Sprague-Dawley (SD) controls. Already by wk 5, untreated dTGR showed increased perivascular and interstitial fibrosis, connective tissue growth factor expression, and monocyte infiltration compared with SD rats, differences that progressed through time. Left-ventricular mRNA expression of potassium channel subunit Kv4.3 and gap-junction protein connexin 43 were significantly reduced in dTGR compared with Los-treated dTGR and SD. CMFM showed that depolarization and repolarization were prolonged and inhomogeneous. Los ameliorated all disturbances. VT could be induced in 88% of dTGR but only in 33% of Los-treated dTGR and could not be induced in SD. Untreated dTGR show electrical remodeling and probably die from VT. Los treatment reduces myocardial remodeling and predisposition to arrhythmias. ANG II target organ damage induces VT. magnetocardiography; noninvasive mapping; double-transgenic rat model; in vivo electrophysiological study ELECTRICAL REMODELING INVOLVES acquired changes in cardiac structure or function that promote the occurrence of atrial or ventricular cardiac arrhythmias (22). On the molecular level, electrical remodeling involves changes in function and expression of membrane ion channels, gap-junction proteins, Ca 2ϩ -cycling proteins, and extracellular matrix composition. All these factors predispose to arrhythmogenic mechanisms such as early and delayed afterdepolarizations and reentry (13). The multifactorial origin of electrical remodeling has been extensively studied in cardiac ischemia and heart failure. However, electrical remodeling in hypertension is less well defined. Patients with hypertension-induced left-ventricular hypertrophy are at increased risk for arrhythmias, which contribute to a twofold increase in cardiovascular mortality (7). Monitoring electrical remodeling is challenging. The standard 12-lead electrocardiogram (ECG), ECG-based body surface potential mapping, and signal-averaged ECG are correlated with an increased risk to develop malignant arrhythmias. However, the positive predictive accuracy is unacceptably low or not sufficiently tested in randomized trials (14).Multichannel cardiac magnetic field mapping (CMFM) reflects the magnetic fields generated by the myocardial electrical currents occurring during the cardiac cycle. CMFM signals have several advantages: 1) they are littl...

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