Effects of Different Exercise Modalities on Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction

Figure 1. Schematic outline of the present study. At 20 weeks, obese rats were randomly assigned to undergo moderate‐intensity continuous exercise training (MICT) or high‐intensity interval training (HIIT) or to remain sedentary (Sed.). The first part of the study investigates pathological cellular mechanisms of the sedentary obese rats [heart failure with preserved ejection fraction (HFpEF)] vs. their lean litter mates (CT) in early (Figure 2; 21‐week‐old rats) and advanced disease progression (28‐week‐old rats). The second part evaluates how the different modalities of exercise training can alter these pathologies and consecutively change cardiac function in HFpEF.

Figure 2. Representative samples of the experimental protocol (A). Left ventricular cardiomyocytes of 21‐week‐old rats were exposed at 1 Hz electrical stimulation, and cytosolic Ca2+ transients were analysed for their Ca2+ release amplitude (B), time to half peak (TF50; C), time to peak (TTP; D), and Ca2+ decay (tau; E). Consecutively, cells were paced at 3 Hz, and cytosolic Ca2+ transients were analysed for their Ca2+ release amplitude (F), time to half peak (TF50; G), time to peak (TTP; H), and Ca2+ decay (tau; I). Nuclear Ca2+ transients were recorded at 1 Hz electric pacing, and cytosolic Ca2+ transients were analysed for their Ca2+ release amplitude (J), time to half peak (TF50; K), time to peak (TTP; L), and Ca2+ decay (tau; M) determined. Statistical analysis: two‐tailed, unpaired Student's t‐test. P‐values: 10.027, 2 < 0.0001, 30.035, and 40.027. n = cells from 10 animals per group. HFpEF, heart failure with preserved ejection fraction.

Figure 3. Representative samples of the experimental protocol (A). Left ventricular cardiomyocytes of 28‐week‐old rats were exposed to varying pacing frequencies by electrical stimulation, and Ca2+ transients were analysed for their time to peak (TTP; B), Ca2+ release amplitude (C), Ca2+ decay (tau; D), and diastolic Ca2+ (E). Ca2+ leak from the sarcoplasmic reticulum (SR; F) during sodium–Ca2+ exchanger inactivation. Ca2+ load of the SR quantified by application of caffeine (G) and subsequent Ca2+ decay (H). Statistical analysis: two‐way ANOVA followed by post hoc Bonferroni (B–D: 1–5 Hz); two‐tailed, unpaired Student's t‐test (B–D: 1 Hz rec., F–H). P‐values: 10.0001, 2 < 0.0001, 30.001, 40.02, 50.0007, 60.047, 70.02, 80.039, and 90.025. n = cells from four animals per group. (B–E) CT, n = 23; heart failure with preserved ejection fraction (HFpEF), n = 19.

Figure 4. Representative examples of the experimental protocol (A). Ca2+ transients (CaTs) were analysed for their Ca2+ release amplitude (B), the area under the curve (AUC; C), Ca2+ decay during CaTs (tau CaT; D), and diastolic Ca2+ (E). Ca2+ leak from the sarcoplasmic reticulum (SR; F) during sodium–Ca2+ exchanger inactivation. Ca2+ load of the SR quantified by application of caffeine (G) and subsequent Ca2+ decay (H). Statistical analysis: paired, two‐way (B–E: 1–5 Hz) and one‐way ANOVA (B–E: 1–5 Hz rec., F–H) followed by post hoc Bonferroni vs. Sed. P‐values: 10.016, 20.004, 30.006, 40.007, 50.005, 60.04, 70.049, 80.046, 90.028, and 100.006. n = cells from four animals per group. (B–E) Sed., n = 20; moderate‐intensity continuous training (MICT), n = 22; and high‐intensity interval training (HIIT), n = 27.

Figure 5. Echocardiographic evaluation after 8 weeks of exercise training [moderate‐intensity continuous training (MICT) and high‐intensity interval training (HIIT)] or the absence thereof (Sed.). End‐diastolic volume (A; EDV) and stroke volume (B; SV) were calculated from diastolic and systolic volumes, global longitudinal strain (GLS) by speckle tracking (C) and heart rate in beats per minute (b.p.m.; D). Statistical analysis: one‐way ANOVA followed by a post hoc Bonferroni vs. Sed. (A, B) or vs. all groups (C, D). P‐values: 10.03, 20.04, and 30.0004. n = animals.

Figure 6. Representative examples of spontaneous Ca2+ activity during inactivation of the sodium–Ca2+ exchanger (A). Occurrence of Ca2+ sparks (B) and wave propagation velocity [C; high‐intensity interval training (HIIT): insufficient events for quantification]. One‐way ANOVA followed by post hoc Bonferroni vs. Sed. (B) and two‐tailed, unpaired Student's t‐test (C). P‐values: 10.046 and 20.02. n = cells from four animals per group. MICT, moderate‐intensity continuous training.

Figure 7. Ca2+ transients were analysed for their time to reach maximum amplitude (A) and their time to reach half‐maximum amplitude (TF50; B). Example of the spatial distribution of early and late Ca2+ release in left ventricular cardiomyocytes (shown: Sed.), as well as their consecutive beat‐to‐beat variation (C). The amount of early release sites was quantified (>3/10 early release events; D), and their probability of early release was determined in 10 consecutive cycles (E). Statistical analysis: either a two‐way (A–E: 1–5 Hz) or one‐way (A–E: 1 Hz rec.) ANOVA followed by a post hoc Bonferroni vs. Sed. (A–C). P‐values: 10.0494, 20.03, 30.02, and 40.03. n = cells from four animals per group. (A, B) Sed., n = 20; moderate‐intensity continuous training (MICT), n = 22; and high‐intensity interval training (HIIT), n = 27. (D, E) Sed., n = 39; MICT, n = 22; and HIIT, n = 27.