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• W2233154905 abstract "Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFAs produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFAs, we shortened the ω3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G protein-coupled receptor for ω3-PUFAs, was sufficient and required to block transforming growth factor β1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF. Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFAs produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFAs, we shortened the ω3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G protein-coupled receptor for ω3-PUFAs, was sufficient and required to block transforming growth factor β1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF. Heart failure (HF) is a complex and heterogeneous syndrome, and two broadly defined phenotypes have emerged in the last 10 years: HF with reduced ejection fraction (EF) and HF with preserved EF (HFpEF). Currently, over half of all HF diagnoses are HFpEF, and incidence is increasing rapidly as the population ages (1.Owan T.E. Hodge D.O. Herges R.M. Jacobsen S.J. Roger V.L. Redfield M.M. Trends in prevalence and outcome of heart failure with preserved ejection fraction.N. Engl. J. Med. 2006; 355: 251-259Crossref PubMed Scopus (3170) Google Scholar, 2.Steinberg B.A. Zhao X. Heidenreich P.A. Peterson E.D. Bhatt D.L. Cannon C.P. Hernandez A.F. Fonarow G.C. Get With the Guidelines Scientific Advisory Committee and Investigators Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.Circulation. 2012; 126: 65-75Crossref PubMed Scopus (583) Google Scholar). Generally, patients with HFpEF are older, female, and more likely to have hypertension, renal disease, atrial fibrillation, and/or pulmonary disease (2.Steinberg B.A. Zhao X. Heidenreich P.A. Peterson E.D. Bhatt D.L. Cannon C.P. Hernandez A.F. Fonarow G.C. Get With the Guidelines Scientific Advisory Committee and Investigators Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.Circulation. 2012; 126: 65-75Crossref PubMed Scopus (583) Google Scholar). More importantly, standard HF therapies show no efficacy in HFpEF (3.From A.M. Borlaug B.A. Heart failure with preserved ejection fraction: pathophysiology and emerging therapies.Cardiovasc. Ther. 2011; 29: e6-e21Crossref PubMed Scopus (24) Google Scholar, 4.Senni M. Paulus W.J. Gavazzi A. Fraser A.G. Diez J. Solomon S.D. Smiseth O.A. Guazzi M. Lam C.S. Maggioni A.P. et al.New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes.Eur. Heart J. 2014; 35: 2797-2815Crossref PubMed Scopus (263) Google Scholar). Numerous studies have established that ω3-PUFAs, EPA, and DHA are cardioprotective [reviews (5.Harris W.S. Poston W.C. Haddock C.K. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events.Atherosclerosis. 2007; 193: 1-10Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 6.Lavie C.J. Milani R.V. Mehra M.R. Ventura H.O. Omega-3 polyunsaturated fatty acids and cardiovascular diseases.J. Am. Coll. Cardiol. 2009; 54: 585-594Crossref PubMed Scopus (474) Google Scholar, 7.Mozaffarian D. Wu J.H. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events.J. Am. Coll. Cardiol. 2011; 58: 2047-2067Crossref PubMed Scopus (1218) Google Scholar)]. Four large randomized clinical trials demonstrated that increased blood levels of ω3-PUFAs correlate with reduced mortality and hospitalizations in coronary heart disease (CHD) (8.Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3729) Google Scholar, 9.Burr M.L. Fehily A.M. Gilbert J.F. Rogers S. Holliday R.M. Sweetnam P.M. Elwood P.C. Deadman N.M. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).Lancet. 1989; 2: 757-761Abstract PubMed Scopus (2320) Google Scholar, 10.Mozaffarian D. Lemaitre R.N. King I.B. Song X. Spiegelman D. Sacks F.M. Rimm E.B. Siscovick D.S. Circulating long-chain omega-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study.Ann. Intern. Med. 2011; 155: 160-170Crossref PubMed Scopus (142) Google Scholar, 11.Yokoyama M. Origasa H. Matsuzaki M. Matsuzawa Y. Saito Y. Ishikawa Y. Oikawa S. Sasaki J. Hishida H. Itakura H. et al.Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1936) Google Scholar). This is supported by several meta-analyses indicating that ω3-PUFAs reduce the risk of CHD by preventing sudden death (12.Mozaffarian D. Rimm E.B. Fish intake, contaminants, and human health: evaluating the risks and the benefits.JAMA. 2006; 296: 1885-1899Crossref PubMed Scopus (1541) Google Scholar, 13.Harris W.S. Mozaffarian D. Lefevre M. Toner C.D. Colombo J. Cunnane S.C. Holden J.M. Klurfeld D.M. Morris M.C. Whelan J. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids.J. Nutr. 2009; 139: 804S-819SCrossref PubMed Scopus (281) Google Scholar, 14.He K. Song Y. Daviglus M.L. Liu K. Van Horn L. Dyer A.R. Greenland P. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies.Circulation. 2004; 109: 2705-2711Crossref PubMed Scopus (670) Google Scholar, 15.León H. Shibata M.C. Sivakumaran S. Dorgan M. Chatterley T. Tsuyuki R.T. Effect of fish oil on arrhythmias and mortality: systematic review.BMJ. 2008; 337: a2931Crossref PubMed Scopus (179) Google Scholar, 16.Marik P.E. Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review.Clin. Cardiol. 2009; 32: 365-372Crossref PubMed Scopus (283) Google Scholar). Few studies have examined ω3-PUFAs in HF, but the most prominent is GISSI-HF (17.Tavazzi L. Maggioni A.P. Marchioli R. Barlera S. Franzosi M.G. Latini R. Lucci D. Nicolosi G.L. Porcu M. Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.Lancet. 2008; 372: 1223-1230Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar). In GISSI-HF, ω3-PUFAs reduced total mortality 9% and cardiovascular mortality 8%, on top of standard care, whereas statins had no effect (17.Tavazzi L. Maggioni A.P. Marchioli R. Barlera S. Franzosi M.G. Latini R. Lucci D. Nicolosi G.L. Porcu M. Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.Lancet. 2008; 372: 1223-1230Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar). Another small clinical trial examined the effects of ω3-PUFAs on left ventricular systolic function in patients with stable class II-IV NYHA HF secondary to nonischemic dilated cardiomyopathy (18.Nodari S. Triggiani M. Campia U. Manerba A. Milesi G. Cesana B.M. Gheorghiade M. Dei Cas L. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy.J. Am. Coll. Cardiol. 2011; 57: 870-879Crossref PubMed Scopus (167) Google Scholar). After 1 year, ω3-PUFAs significantly improved left ventricular EF, peak VO2, exercise duration, and mean NYHA functional class. While results from the GISSI-HF trial and this more recent study are promising, neither addressed patients with HFpEF (17.Tavazzi L. Maggioni A.P. Marchioli R. Barlera S. Franzosi M.G. Latini R. Lucci D. Nicolosi G.L. Porcu M. Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.Lancet. 2008; 372: 1223-1230Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar, 18.Nodari S. Triggiani M. Campia U. Manerba A. Milesi G. Cesana B.M. Gheorghiade M. Dei Cas L. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy.J. Am. Coll. Cardiol. 2011; 57: 870-879Crossref PubMed Scopus (167) Google Scholar). A limited number of studies have examined ω3-PUFAs mechanistically in cell or animal models of HF. Further, due to the phenotypic variation and complicated pathophysiology of HFpEF, no animal models perfectly replicate remodeling in HFpEF (19.Butler J. Fonarow G.C. Zile M.R. Lam C.S. Roessig L. Schelbert E.B. Shah S.J. Ahmed A. Bonow R.O. Cleland J.G. et al.Developing therapies for heart failure with preserved ejection fraction: current state and future directions.JACC Heart Fail. 2014; 2: 97-112Crossref PubMed Scopus (248) Google Scholar, 20.Horgan S. Watson C. Glezeva N. Baugh J. Murine models of diastolic dysfunction and heart failure with preserved ejection fraction.J. Card. Fail. 2014; 20: 984-995Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). However, transverse aortic constriction (TAC), a surgical model of afterload-induced HF, approximates some aspects of remodeling in HFpEF (20.Horgan S. Watson C. Glezeva N. Baugh J. Murine models of diastolic dysfunction and heart failure with preserved ejection fraction.J. Card. Fail. 2014; 20: 984-995Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). TAC induces hypertrophy, interstitial cardiac fibrosis, and systolic and diastolic dysfunction, which, excluding systolic dysfunction, are common features of HFpEF. Recently, we reported that dietary supplementation with a fish oil (FO) diet rich in ω3-PUFAs prevents interstitial fibrosis and cardiac systolic and diastolic dysfunction induced by TAC (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). More importantly, we identified a direct effect of ω3-PUFAs on cardiac fibroblasts to inhibit myofibroblast transformation and, thereby, prevent fibrosis. Prevention of fibrosis and diastolic dysfunction in the TAC model by ω3-PUFA supplementation might suggest that ω3-PUFA supplementation could be a novel therapy for HFpEF. However, the ω3-index [erythrocyte ω3-PUFA levels defined by (DHA + EPA)/total FAs] and ω3-PUFA levels in heart tissue (15.3 and 36.5%, respectively) achieved in our previous study were well above the basal ω3-index observed in most human populations (∼4% in US; ∼9% in Japan), and significantly higher than the maximal cardioprotective effects in CHD associated with an ω3-index ≥8% (22.Harris W.S. The omega-3 index: clinical utility for therapeutic intervention.Curr. Cardiol. Rep. 2010; 12: 503-508Crossref PubMed Scopus (98) Google Scholar). This raised several important questions including: 1) whether the cardioprotective effects we observed were due to the supra-physiologic ω3-levels; 2) which ω3-PUFA(s) mediated prevention of fibrosis; and 3) whether improvement in function was due solely to prevention of fibrosis, or whether ω3-PUFAs have a protective effect on function independent of prevention of fibrosis. To address these questions, we examined ventricular remodeling following TAC in mice fed diets supplemented with EPA or DHA, and control mice fed the standard ω3-diet (FO) or control diet [corn oil (CO)] from our previous study (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). To achieve more clinically relevant ω3-PUFA levels, we reduced the pre-TAC diet regimen to 2 weeks and continued the diet for 6 weeks post-TAC. Briefly, the shorter diet regimen produced ω3-PUFA levels closer to humans treated with ω3-PUFAs (∼10%). Further, we found that EPA prevented fibrosis, but did not accumulate in cardiac myocytes or nonmyocytes (fibroblasts), the traditional mechanism of action. Alternatively, we found that FFA receptor (FFAR)4, a G protein-coupled receptor (GPR) for long-chain FAs, including ω3-PUFAs, was both sufficient and required to prevent fibrotic signaling in cultured adult cardiac fibroblasts, suggesting a novel mechanism of action. In this study, 97 8-week-old C57BL/6J mice were randomly divided into four groups and started on diets supplemented with ω3-PUFAs (see Diets below). After 2 weeks, mice were subjected to TAC (see TAC below) and diets were continued for an additional 6 weeks. All procedures on animals conformed to the Public Health Service Policy on Humane Care and Use of Laboratory Animals and were reviewed and approved by the Institutional Animal Care and Use Committee at Sanford Research. Each diet contained 4% by weight test oil: 1) CO, 40 g CO per kilogram; 2) FO, 12 g menhaden oil and 28 g CO per kilogram; 3) EPA, 1.9 g EPA and 38.1 g CO per kilogram; and 4) DHA, 1.3 g DHA and 38.7 g CO per kilogram) (Dyets, Bethlehem, PA). The levels of EPA and DHA in the experimental diets were based on the relative amounts of EPA and DHA in the FO diet. TAC surgery was performed as previously described (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar, 23.O'Connell T.D. Ishizaka S. Nakamura A. Swigart P.M. Rodrigo M.C. Simpson G.L. Cotecchia S. Rokosh D.G. Grossman W. Foster E. et al.The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse.J. Clin. Invest. 2003; 111: 1783-1791Crossref PubMed Scopus (163) Google Scholar, 24.O'Connell T.D. Swigart P.M. Rodrigo M.C. Ishizaka S. Joho S. Turnbull L. Tecott L.H. Baker A.J. Foster E. Grossman W. et al.Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload.J. Clin. Invest. 2006; 116: 1005-1015Crossref PubMed Scopus (120) Google Scholar, 25.Nakamura A. Rokosh D.G. Paccanaro M. Yee R.R. Simpson P.C. Grossman W. Foster E. LV systolic performance improves with development of hypertrophy after transverse aortic constriction in mice.Am. J. Physiol. Heart Circ. Physiol. 2001; 281: H1104-H1112Crossref PubMed Google Scholar). TAC was validated by examining the relationship between aortic velocity and hypertrophy [heart weight-to-body weight ratio (HW/BW)], fibrosis, systolic dysfunction (EF), and diastolic dysfunction [early mitral valve filling velocity to early mitral annular tissue velocity (E/E‘)], which all showed a direct (HW/BW, fibrosis, E/E‘) or indirect correlation (EF) (supplementary Fig. 1). Additional details are included in the supplementary Methods. Blood was collected from the left ventricle for quantification of FA in erythrocytes. Five TAC mice from each diet group were used to quantitate FAs in cardiac myocytes and nonmyocytes (fibroblasts). Myocytes and nonmyocytes (fibroblasts) were isolated as previously described (26.O'Connell T.D. Rodrigo M.C. Simpson P.C. Isolation and culture of adult mouse cardiac myocytes.Methods Mol. Biol. 2007; 357: 271-296PubMed Google Scholar). FA levels were measured as previously described (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar, 27.Harris W.S. Sands S.A. Windsor S.L. Ali H.A. Stevens T.L. Magalski A. Porter C.B. Borkon A.M. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation.Circulation. 2004; 110: 1645-1649Crossref PubMed Scopus (286) Google Scholar). Additional details are included in the supplementary Methods. Echocardiography was performed before TAC and weekly after TAC using a Vevo 2100 system (VisualSonics, Toronto, Canada) with the MS250 (9–18 MHz) and MS400 (18–38 MHz) transducers. For all measurements, mice were anesthetized with isoflurane, gently restrained, and echocardiographic images were captured as mice were recovering from anesthesia to achieve a target heart rate of 500–550 bpm. Additional details on specific parameters measured are included in the supplementary Methods. Six weeks after TAC, hearts were arrested in diastole and perfusion-fixed for 20 min with 4% paraformaldehyde (Electron Microscopy Sciences, Hatfield, PA). Hearts were paraffin-embedded, sectioned, and stained by the Sanford-Burnham Histopathology Core (La Jolla, CA). Paraffin-embedded transverse sections were stained with picrosirius red (collagen stain) to quantitate ventricular fibrosis. Ventricular fibrosis (as percent of total ventricular area) was quantified using Fiji software (National Institutes of Health). Ventricular fibrosis was quantified using images captured at 4× magnification and included both the right and left ventricle. The threshold settings were adjusted to highlight and calculate the total tissue area or the picrosirius red positively stained area. Total RNA was extracted from heart tissue or freshly isolated cardiac myocytes and nonmyocytes (fibroblasts) [cell isolations were as previously described (26.O'Connell T.D. Rodrigo M.C. Simpson P.C. Isolation and culture of adult mouse cardiac myocytes.Methods Mol. Biol. 2007; 357: 271-296PubMed Google Scholar)] using TRIzol reagent (Life Technologies) followed by RNeasy fibrous tissue mini kit (Qiagen). Total RNA was quantified using a NanoDrop ND-2000 spectrophotometer (Thermo Scientific). Quantitative RT-PCR for FFAR1, FFAR2, FFAR3, and FFAR4 gene expression in whole hearts was measured by the Genomic-Microarray/qPCR Core at the Sanford/Burnham Institute (La Jolla, CA), as previously described (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar, 28.Chen Q. Williams R. Healy C.L. Wright C.D. Wu S.C. O'Connell T.D. An association between gene expression and better survival in female mice following myocardial infarction.J. Mol. Cell. Cardiol. 2010; 49: 801-811Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Additional details are included in the supplementary Methods. Cardiac fibroblasts were isolated from hearts of a group of untreated C57BL/6J mice and cultured as previously described (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). Where indicated, fibroblasts were transfected with 5 nM siRNA directed against FFAR4 or control scrambled siRNA using Lipofectamine 2000 (Life Technologies). After 48 h, fibroblasts were treated with transforming growth factor β1 (TGFβ1) (1 ng/ml) and GW9508 (1–50 μM), an FFAR1/4 agonist. After 48 h, myofibroblast transformation was assessed by collagen I expression, fibroblast proliferation, and α-smooth muscle actin staining, as previously described (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). Additional details are included in the supplementary Methods. Results are presented as mean ± SEM or with 95% confidence interval, as indicated in the figure legends. Data were analyzed by unpaired t-test with Welch's correction, one-way ANOVA, or two-way ANOVA with a Tukey post-test, or linear/non-linear regression, as indicated in the figure legends. Data were tested for normal distribution with the D'Agostino and Pearson test. In cases where data were not normally distributed, data were log-transformed and anti-log values were presented. The unpaired t-test with Welch's correction was used to adjust for small n values in the sham group. Where explanatory models were developed, Mallow's Cp was used to identify the most parsimonious model with the least bias at the lowest parameter (p), where Cp < p. P < 0.05 was considered significant. Data were analyzed using Prism (GraphPad Software, version 6.0) or JMP Pro (SAS Institute, version 10.0.2). We previously demonstrated that 12 weeks of dietary supplementation with ω3-PUFAs produced high levels of ω3-PUFAs that prevented fibrosis and contractile dysfunction in mice subjected to pathologic pressure overload by TAC (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). However, ω3-PUFA levels achieved by 12 weeks of dietary supplementation were well above levels observed in most human populations. To achieve ω3-levels more relevant to human populations, we reduced the duration of dietary supplementation before TAC to 2 weeks, and continued for 6 weeks following surgery (timeline, Fig. 1A). To delineate the effects of specific ω3-PUFAs on preventing pathologic remodeling following TAC, mice were fed diets supplemented with specific ω3-PUFAs, including EPA or DHA, while control mice were fed diets supplemented with either CO or FO, as we previously described (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). The shorter diet regimen resulted in lower ω3-PUFA levels (EPA + DHA) in erythrocytes and heart tissue for mice fed the FO diet [FO ω3-PUFA levels (10.02 ± 0.74%, 24.00 ± 1.51%), CO ω3-PUFA levels (5.10 ± 0.60%, 10.79 ± 0.36%) for erythrocytes and heart, respectively (Fig. 1B; supplementary Tables 2, 4)], which was roughly half the increase achieved in our previous study (compare with red dashed lines) (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar). With only 2 weeks of dietary supplementation before TAC versus 8 weeks in our previous study, ω3-PUFA levels were also likely significantly lower at the time of surgery in this study. Dietary supplementation with EPA or DHA alone also significantly increased ω3-PUFA levels (EPA + DHA) in erythrocytes and heart to a similar degree (Fig. 1B; and supplementary Tables 2, 4). Decreased levels of arachidonic acid (AA) (ω6) and docosapentaenoic acid (ω6) primarily offset the increased levels of ω3-PUFAs (supplementary Table 2). To validate the EPA- and DHA-specific diets, we also measured erythrocyte levels of each FA from each diet group. As expected, erythrocyte EPA or DHA levels were significantly increased in mice fed each respective diet (Fig. 1C, supplementary Table 2). Pathologic remodeling induced by TAC is characterized by concentric remodeling/hypertrophy, interstitial fibrosis, and systolic and diastolic dysfunction. Six weeks after TAC, mice fed the control CO diet exhibited a significant increase in heart weight (HW) and heart weight-to-body weight ratio (HW/BW), a significant increase in ventricular fibrosis, a significant drop in EF, and a significant increase in E/E' versus sham animals on the CO diet (Table 1), all indicative of pathologic remodeling. As with our prior study (21.Chen J. Shearer G.C. Chen Q. Healy C.L. Beyer A.J. Nareddy V.B. Gerdes A.M. Harris W.S. O'Connell T.D. Wang D. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.Circulation. 2011; 123: 584-593Crossref PubMed Scopus (125) Google Scholar), dietary supplementation with ω3-PUFAs (FO, EPA, or DHA) had no effect on TAC-induced hypertrophy (HW or HW/BW). Interestingly, TAC-induced fibrosis (percent ventricular area in the TAC CO group) was not prevented by dietary supplementation with either the FO or DHA diets, but the degree of fibrosis in mice fed the EPA diet was similar to sham (sham CO: 1.46 ± 0.25%; EPA: 1.44 ± 0.29%), although this did not reach significance due to variability in the fibrotic response (one way ANOVA, comparing CO, FO, EPA, DHA; P = 0.22; Table 1). Alternatively, we examined the relationship between the abundance of erythrocyte ω3-PUFAs (defined as percent mass of total FAs) and the degree of fibrosis (Fig. 2A, B; EPA and DHA, respectively). Importantly, we found a significant inverse correlation between erythrocyte EPA levels and total fibrosis (n = 48, P = 0.027) that was not evident for DHA levels (n = 48, P = 0.471) (Fig. 2A, B). We next asked whether the inverse relationship between fibrosis and EPA abundance was different within each group, using model-fitting to test whether this simple relationship between percent EPA and percent fibrosis was sufficient or whether the dietary group provided a better explanation (Fig. 2C). Both diets supplemented with EPA (FO and EPA) were inversely correlated to myocardial fibrosis; however, the FO diet, providing both DHA and EPA, had low fibrosis at lower EPA levels than the EPA diet. Neither diet lacking EPA reduced fibrosis. Therefore, the current study indicated that EPA, but not DHA, prevents TAC-induced fibrosis, with a possible role for DHA in sensitizing the EPA response.TABLE 1Summary of the effects of ω3-PUFA dietary supplementation on cardiac morphology and function following TACCO ShamCO TACFO TACEPA TACDHA TACRBC FA%n—18201516EPA—0.27 ± 0.051.54 ± 0.04bP < 0.05 versus CO TAC (one-way ANOVA, Tukey post-test).2.71 ± 0.13bP < 0.05 versus CO TAC (one-way ANOVA, Tukey post-test).0.46 ± 0.09DHA—4.83 ± 0.598.47 ± 0.79bP < 0.05 versus CO TAC (one-" @default.
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