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. 2024 Jun 29;16(13):2087.
doi: 10.3390/nu16132087.

High-Fat Diet Augments Myocardial Inflammation and Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy

Ann M Centner  1 , Emily A Shiel  1 , Waleed Farra  1 , Elisa N Cannon  1 , Maicon Landim-Vieira  1 , Gloria Salazar  2 , Stephen P Chelko  1   3
Affiliations

High-Fat Diet Augments Myocardial Inflammation and Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy

Ann M Centner et al. Nutrients. .

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease's progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.

Keywords: Desmoglein-2; arrhythmogenic cardiomyopathy; high-fat diet; lipids; myocardium.

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Conflict of interest statement

S.P.C. is on the advisory board for Rejuvenate Bio and Who We Play For. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Echo- and electrocardiographic alterations in Dsg2mut/mut mice fed HFD. (A) Representative short-axis m-mode echocardiograms (Echos) from 16-week-old WT mice fed chow (WT + chow) and Dsg2mut/mut mice fed chow (Dsg2mut/mut + chow) or HFD (Dsg2mut/mut + HFD). (B) Cardiac function assessed as percent left ventricular ejection fraction (%LVEF), prior to diet intervention (8 weeks of age) and at study endpoint (16 weeks of age). (C) Representative signal-averaged electrocardiograms (SAECGs) from 16-week-old mice and indices of interest altered by an HFD, including (D) P-wave duration, (E) P-wave amplitude, and (F) S-wave amplitude. ms, millisecond; mv, millivolt. Data presented as mean ± SEM; n ≥ 7 mice/cohort/parameter; ns, not significant; ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001 via one-way ANOVA with Tukey’s post hoc.
Figure 2
Figure 2
Echocardiographic correlations in Dsg2mut/mut mice. (A,B) Pearson’s correlation matrix from echocardiographic indices taken from 16-week-old HFD-fed Dsg2mut/mut mice (n ≥ 7 mice/parameter). Pearson’s correlation (A) p-values and (B) r-values. Positive correlations, blue; negative correlations, red. Note: (C) relative wall thickness (RWT) and (D) LV fractional shortening (%LVFS) demonstrated a strong correlation with %LVEF via Pearson’s r correlation analysis. n ≥ 7 mice/cohort/parameter. Square boxes, each HFD-fed Dsg2mut/mut mouse’s individual data points; solid and dashed lines, the linear regression line (i.e., slope) and 95% confidence interval, respectively.
Figure 3
Figure 3
Lipid perturbations and ejection fraction correlations in Dsg2mut/mut mice. (A,B) Pearson’s correlation matrix circulating for lipids and plasma markers from 16-week-old HFD-fed Dsg2mut/mut mice (n ≥ 4 mice/parameter) in relation to %LVEF. Pearson’s correlation (A) p-values and (B) r-values. Positive correlations, blue; negative correlations, red. For (A), any correlation deemed significant via * p ≤ 0.05. (C–E) HFD-fed augmented the levels of circulating TC (mg/dL), LDL (mg/dL), and HDL (mg/dL), respectively, in Dsg2mut/mut mice compared to all cohorts. (E) Of note, HDL levels correlated with increased %LVEF (r = 0.83). Square boxes, each HFD-fed Dsg2mut/mut mouse’s individual data points; solid and dashed lines, the linear regression line (i.e., slope) and 95% confidence interval, respectively. For (C–E), data presented as mean ± SEM; ns, not significant; * p ≤ 0.05, ** p ≤ 0.01, and **** p ≤ 0.0001 via one-way ANOVA with Tukey’s post hoc. N ≥ 4mice/cohort/parameter. TC, total cholesterol; TG, triglycerides; HDL, LDL, and VLDL, high-, low-, and very low-density lipoproteins, respectively; nHDL-c, non-HDL cholesterol; TC/H, TC/HDL; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Glu, glucose.
Figure 4
Figure 4
HFD-induced exacerbation of inflammatory cytokines in Dsg2mut/mut mice. (A) Representative Masson’s trichrome immunostained hearts from 16-week-old mice. (B) Note the inability of an HFD to induce further myocardial fibrosis in Dsg2mut/mut mice. ns, not significant; ** p ≤ 0.01, **** p ≤ 0.0001 via one-way ANOVA with Tukey’s post hoc. (C) Representative cytokine arrays and (D) grouped data from cardiac lysates from 16-week-old mice. Reference bands (R. Band). Data presented as mean ± SEM as fold change to WT controls; * p ≤ 0.05 any cohort vs. WT + chow; † p ≤ 0.05 Dsg2mut/mut + HFD vs. Dsg2mut/mut + chow. n ≥ 7 mice/cohort/parameter.
Figure 5
Figure 5
Myocardial inflammatory markers grouped by physiological role in cell signaling. (A–F) Levels of cardiac inflammatory cytokines (expressed as pg/mL) from 16-week-old mice grouped by role in inflammation. Data presented as mean ± SEM; n ≥ 7 mice/cohort/parameter; * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, and **** p ≤ 0.0001 via two-way ANOVA with Tukey’s post hoc.
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