Moderate Exercise Training Improves Survival and Ventricular Remodeling in an Animal Model of Left Ventricular Volume Overload

Lachance, Dominic; Plante, Eric; Bouchard-Thomassin, Andrée-Anne; Champetier, Serge; Roussel, Élise; Drolet, Marie‐Claude; Arsenault, Marie; Couët, Jacques

doi:10.1161/circheartfailure.108.845487

Cited by 41 publications

(55 citation statements)

References 37 publications

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“…To our surprise, left ventricular function in hLPL0 mice did not worsen after 6 wk of swim training but actually improved. Our studies with a model of heart failure due specifically to a genetic loss of lipid uptake by the heart are consistent with other studies in both animal models of heart failure (11,32) and heart failure patients that found exercise-induced improvements in cardiac ejection fraction (18,24,55).…”

Section: Discussionsupporting

confidence: 91%

Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function

Khan

Yan

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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IJ.Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function. Am J Physiol Endocrinol Metab 305: E1339 -E1347, 2013. First published October 1, 2013; doi:10.1152/ajpendo.00349.2013.-Hearts utilize fatty acids as a primary source of energy. The sources of those lipids include free fatty acids and lipoprotein triglycerides. Deletion of the primary triglyceride-hydrolyzing enzyme lipoprotein lipase (LPL) leads to cardiac dysfunction. Whether heart LPL-knockout (hLPL0) mice are compromised due a deficiency in energetic substrates is unknown. To test whether alternative sources of energy will prevent cardiac dysfunction in hLPL0 mice, two different models were used to supply nonlipid energy. 1) hLPL0 mice were crossed with mice transgenically expressing GLUT1 in cardiomyocytes to increase glucose uptake into the heart; this cross-corrected cardiac dysfunction, reduced cardiac hypertrophy, and increased myocardial ATP. 2) Mice were randomly assigned to a sedentary or training group (swimming) at 3 mo of age, which leads to increased skeletal muscle production of lactate. hLPL0 mice had greater expression of the lactate transporter monocarboxylate transporter-1 (MCT-1) and increased cardiac lactate uptake. Compared with hearts from sedentary hLPL0 mice, hearts from trained hLPL0 mice had adaptive hypertrophy and improved cardiac function. We conclude that defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure. triglyceride; heart failure; glucose; lactate; energetics; glucose transporters IN THE HEALTHY ADULT HUMAN HEART, most of the energy required for normal cellular processes is derived from the uptake and oxidation of fatty acids (FAs), with the remainder being contributed by glucose, lactate, and amino acids (36). FAs are delivered to the heart either as free fatty acids (FFAs) conjugated to albumin or via lipoprotein lipase (LPL)-mediated hydrolysis of lipoproteins, with subsequent uptake by FAT/CD36, other FA transporters, and nonreceptor mediated pathways (5).Cardiomyocyte deletion of LPL (hLPL0) leading to reduced triglyceride (TG) lipolysis increased cardiac glucose uptake and reduced expression of several peroxisomal proliferatoractivated receptor (PPAR) regulated genes (1). hLPL0 hearts developed reduced ejection fraction (2) and were unable to compensate when subjected to increased afterload due to aortic coarctation or hypertension (56). These data suggest that TG is an important source of lipid for cardiac energy.In heart failure, traditional cardiac substrate usage of FAs is perturbed, and as a result the heart shifts away from FA oxidation to glucose utilization. These changes in heart energy use have been studied experimentally in isolated hearts using buffers containing FFAs (35). W...

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Section: Discussionsupporting

confidence: 91%

Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function

Khan

Yan

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Although interstitial fibrosis is not an early feature of this animal model of eccentric LV remodeling, significant accumulation of collagen is present in later stages (≥6 months). 16,22 Our results suggest that the dilated hearts of Cpt-treated AR animals tolerated the abnormal hemodynamic overload and maintained a near normal myocardial metabolic profile. We previously showed that blood pressure in AR animals treated with Cpt is only slightly reduced and had similar findings in this protocol.…”

Section: Discussionmentioning

confidence: 65%

“…Our findings also confirm our previous observations of the benefits of Cpt in AR. 5,22 The controversy regarding the efficacy of vasodilators, including ACEI in the treatment of AR, is far from resolved. Recently, a meta-analysis of all the randomized clinical trials that evaluated vasodilators in AR 23 showed that the evidence points toward the efficacy of vasodilators although a wide discrepancy exists between the trials' design and results.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II–Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling, and Myocardial Energetics in Experimental Aortic Regurgitation

Arsenault

Zendaoui

Roussel

et al. 2013

Circ: Heart Failure

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Background-Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation. Methods and Results-Forty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by µ positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use. Conclusions-In a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial. (Circ Heart Fail. 2013;6:1021-1028.)

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“…Groban et al (Groban et al 2008) performed a 4-week treadmill running program with 6 and 28 months old Fischer 344 × Brown Norway rats resulting in improved mitral annular descent (e′) with older rats similar to the young adult rats without improvements in filling pressures, or E/e′ ratios. Lachance, et al (Lachance et al 2009) required adult rats to train at a moderate intensity for 9 months or remain sedentary and observed significant improvements in LV diastolic parameters as early as 3 months into the study period. In addition to improved LV filling characteristics, these authors noted a reduction in myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Altered left ventricular performance in aging physically active mice with an ankle sprain injury

Turner

Guderian

Wikstrom

et al. 2016

AGE

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We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p < 0.0001). Beginning at 6 months of age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p < 0.0001) beginning at 9 months of age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p < 0.0001), with higher ratios for the SHAM mice and lower ratios for the ATFL/CFL and SHAMSED mice in response to physical activity beginning at 9 months of age. Passive-toactive filling velocity ratio decreased with age (p < 0.0001). Regular physical activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan.

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Moderate Exercise Training Improves Survival and Ventricular Remodeling in an Animal Model of Left Ventricular Volume Overload

Abstract: Background: Exercise training has beneficial effects in patients with heart failure

Cited by 41 publications

References 37 publications

Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function

Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function

Angiotensin II–Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling, and Myocardial Energetics in Experimental Aortic Regurgitation

Altered left ventricular performance in aging physically active mice with an ankle sprain injury

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