Protective Effects of a Discontinuous Treatment with Alpha-Lipoic Acid in Obesity-Related Heart Failure with Preserved Ejection Fraction, in Rats

Abstract

Obesity induces hemodynamic and humoral changes that are associated with functional and structural cardiac remodeling, which ultimately result in the development of heart failure (HF) with preserved ejection fraction (HFpEF). In recent years, pharmacological studies in patients with HFpEF were mostly unsatisfactory. In these conditions, alternative new therapeutic approaches are necessary. The aim of our study was (1) to assess the effects of obesity on heart function in an experimental model and (2) to evaluate the efficacy of an alpha-lipoic acid (ALA) antioxidant treatment. Sprague-Dawley rats (7 weeks old) were either included in the control group (n = 6) or subjected to abdominal aortic banding (AAB) and divided into three subgroups, depending on their diet: standard (AAB + SD, n = 8), hypecaloric (AAB + HD, n = 8) and hypercaloric with discontinuous ALA treatment (AAB + HD + ALA, n = 9). Body weight (BW), glycemia, echocardiography parameters and plasma hydroperoxides were monitored throughout the study. After 36 weeks, plasma adiposity (leptin and adiponectin) and inflammation (IL-6 and TNF-alpha) markers, together with B-type natriuretic peptide and oxidative stress markers (end-products of lipid peroxidation and endogenous antioxidant systems) were assessed. Moreover, cardiac fiber diameters were measured. In our experiment, diet-induced obesity generated cardiometabolic disturbances, and in association with pressure-overload induced by AAB, it precipitated the onset of heart failure, cardiac hypertrophy and diastolic dysfunction, while producing a pro-oxidant and pro-inflammatory plasmatic status. In relationship with its antioxidant effects, the chronic ALA-discontinuous treatment prevented BW gain and decreased metabolic and cardiac perturbations, confirming its protective effects on the cardiovascular system.

Keywords: alpha-lipoic acid; antioxidants; heart failure with preserved ejection fraction; obesity; oxidative stress.

Figure 1

Experimental protocol. AAB—abdominal aortic banding, W—week, Echo—cardiovascular echography, SBP—systolic blood pressure, OGTT—oral glucose tolerance test, ALA—alpha-lipoic acid.

Figure 2

Evolution of (a) Body weight, (b) Pellets consumption (g/rat/3 days), (c) Energy intake from diet (kJ/g) and (d) Energy intake from diet fat (kJ% fat) in the 4 groups of rats evaluated. ** p < 0.01: AAB + HD vs. AAB + SD and Control groups; ^&& p < 0.01: AAB + HD + ALA vs. AAB + HD; ^$ p < 0.05, ^$$$ p < 0.001: AAB + HD and AAB + HD + ALA vs. Control and AAB + SD (two-factor repeated measures ANOVA).

Figure 3

Evolution of systolic blood pressure (SBP) during the first 8 weeks of the study. ** p < 0.01: AAB + HD vs. AAB + SD and Control groups; ^&& p < 0.01: AAB + HD + ALA vs. AAB + HD (two-factor repeated measures ANOVA).

Figure 4

Evolution of structural echocardiographic parameters at 12-, 20-, 28- and 36-weeks of the study: (a) Posterior wall thickness; (b) Interventricular septum thickness; (c) End-diastolic LV volume; (d) End-systolic LV volume; (e) LV mass. ^# p < 0.05: vs. Control, * p < 0.05: vs. AAB + SD and Control; ^& p < 0.05: vs. AAB + HD (one-factor ANOVA).

Figure 5

Hypertrophy echocardiographic markers at 36 weeks of study: (a) Relative wall thickness, (b) Left ventricular mass index (g/mL) (one-factor ANOVA).

Figure 6

Evolution of functional echocardiographic parameters at 12-, 20-, 28- and 36-weeks of the study: (a) Early-to-late LV filling ratio (E/A); (b) Early-to-late LV diastolic relaxation ratio (e′/a′ratio); (c) Mitral valve flow deceleration (MVdec) evaluated at W36; (d) Tei index evaluated at W36 (e) Left ventricular ejection fraction (EF %). ^# p < 0.05: vs. Control, * p < 0.05: vs. AAB + SD and Control; ^& p < 0.05: vs. AAB + HD (one-factor ANOVA).

Figure 7

(a) Evolution of glycemia over a period of 36 weeks and (b) Evaluation of glycemia by the oral glucose tolerance test (OGTT) in W34 of the study. * p < 0.05, *** p < 0.001: AAB + HD vs. AAB + SD and Control groups; ^$$$ p < 0.001: AAB + HD and AAB + HD + ALA vs. AAB + SD and Control groups; ^& p < 0.05: AAB + HD + ALA vs. AAB + HD (two-factor repeated measures ANOVA).

Figure 8

Adiposity markers: (a) Leptin, (b) Adiponectin and (c) Adiponectin/leptin ratio (one-factor ANOVA).

Figure 9

Plasma inflammatory markers: (a) TNF-α and (b) IL-6 (one-factor ANOVA).

Figure 10

(a) Plasma Brain Natriuretic Peptide and (b) Plasma Angiotensin II levels (one-factor ANOVA).

Figure 11

Oxidative stress markers: (a) Plasma Hydroperoxides (“FORT” test), (b) Plasma Malondialdehyde (MDA), (c) GSH/GSSG ratio, (d) Catalase and (e) Total antioxidant capacity (TAC) (one-factor ANOVA).

Figure 12

Plasma Nitrite and Nitrate levels (one-factor ANOVA).

Figure 13

(a) Cardiac fibers diameters (one-factor ANOVA) and (b) Histological features of cardiac fibers in the experimental group. Myocardium fibers (arrow) from: A: AAB + SD group. B: AAB + HD group. C: AAB + HD + ALA group. D: Control group.