title: Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function.
abstract: We have previously reported chronic low-intensity interval exercise training attenuates fibrosis, impaired cardiac mitochondrial function, and coronary vascular dysfunction in miniature swine with left ventricular (LV) hypertrophy (Emter CA, Baines CP. Am J Physiol Heart Circ Physiol 299: H1348-H1356, 2010; Emter CA, et al. Am J Physiol Heart Circ Physiol 301: H1687-H1694, 2011). The purpose of this study was to test two hypotheses: 1) chronic low-intensity interval training preserves normal myocardial oxygen supply/demand balance; and 2) training-dependent attenuation of LV fibrotic remodeling improves diastolic function in aortic-banded sedentary, exercise-trained (HF-TR), and control sedentary male Yucatan miniature swine displaying symptoms of heart failure with preserved ejection fraction. Pressure-volume loops, coronary blood flow, and two-dimensional speckle tracking ultrasound were utilized in vivo under conditions of increasing peripheral mean arterial pressure and β-adrenergic stimulation 6 mo postsurgery to evaluate cardiac function. Normal diastolic function in HF-TR animals was characterized by prevention of increased time constant of isovolumic relaxation, normal LV untwisting rate, and enhanced apical circumferential and radial strain rate. Reduced fibrosis, normal matrix metalloproteinase-2 and tissue inhibitors of metalloproteinase-4 mRNA expression, and increased collagen III isoform mRNA levels (P < 0.05) accompanied improved diastolic function following chronic training. Exercise-dependent improvements in coronary blood flow for a given myocardial oxygen consumption (P < 0.05) and cardiac efficiency (stroke work to myocardial oxygen consumption, P < 0.05) were associated with preserved contractile reserve. LV hypertrophy in HF-TR animals was associated with increased activation of Akt and preservation of activated JNK/SAPK. In conclusion, chronic low-intensity interval exercise training attenuates diastolic impairment by promoting compliant extracellular matrix fibrotic components and preserving extracellular matrix regulatory mechanisms, preserves myocardial oxygen balance, and promotes a physiological molecular hypertrophic signaling phenotype in a large animal model resembling heart failure with preserved ejection fraction.
authors.affiliation: Department of Biomedical Science, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Marshall
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Muller
authors.forename: Maike
authors.initials: M
authors.lastname: Krenz
authors.forename: Laurin M
authors.initials: LM
authors.lastname: Hanft
authors.forename: Kerry S
authors.initials: KS
authors.lastname: McDonald
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dellsperger
authors.forename: Craig A
authors.initials: CA
authors.lastname: Emter
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000235:genetics / Q000502:physiology; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D064211:Connectin; D003971:Diastole / Q000235:genetics / Q000502:physiology*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000534:rehabilitation*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012039:Regional Blood Flow / Q000235:genetics / Q000502:physiology; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013552:Swine; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D016277:Ventricular Function, Left / Q000235:genetics / Q000502:physiology; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D002950:Citrate (si)-Synthase; D024061:Collagen Type III; D064211:Connectin; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2; D009124:Muscle Proteins; D020097:Natriuretic Peptide, Brain; D010100:Oxygen; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4