title: Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure but do not improve survival.
abstract: Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition (MPT), which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients and increases resistance to MPT in animal models. We assessed whether DHA and EPA have similar effects when given individually, and whether they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA, or a 1:1 mixture of DHA + EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298 ± 15 days in untreated hamsters and 335 ± 17, 328 ± 14, and 311 ± 15 days with DHA, EPA, and DHA + EPA, respectively (n = 27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 wk had impaired left ventricular function and increased cardiomyocyte apoptosis compared with normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal and interfibrillar mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, interfibrillar mitochondria from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced MPT, which was completely normalized by treatment with DHA and partially corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters but does not prolong survival or improve cardiac function. This suggest that greater susceptibility to MPT is not a contributor to cardiac pathology and poor survival in heart failure.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Maryland, 20 Penn St., Baltimore, MD 21201, USA.
authors.forename: Tatiana F
authors.initials: TF
authors.lastname: Galvao
authors.forename: Ramzi J
authors.initials: RJ
authors.lastname: Khairallah
authors.forename: Erinne R
authors.initials: ER
authors.lastname: Dabkowski
authors.forename: Bethany H
authors.initials: BH
authors.lastname: Brown
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hecker
authors.forename: Kelly A
authors.initials: KA
authors.lastname: O'Connell
authors.forename: Karen M
authors.initials: KM
authors.lastname: O'Shea
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: Caroline
authors.initials: C
authors.lastname: Daneault
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006224:Cricetinae; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010743:Phospholipids; D049031:Sarcoglycans; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D002118:Calcium