Adverse physiologic effects of Western diet on right ventricular structure and function: role of lipid accumulation and metabolic therapy

Figures

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  Fig. 1.. Western diet (WD) is associated with increased right ventricular systolic pressure (RVSP) and negatively impacts RV structure and function. (a) RVSP was increased in WD-fed mice compared to standard diet (SD) at baseline (P = 0.005). (b) Similarly, there was increased RV hypertrophy with WD compared with SD at baseline (P = 0.02), while the effects were less pronounced with PAB though the trend was similar (P = 0.01). (c) Right ventricular ejection fraction (RVEF) was increased in WD compared to SD (P = 0.03). While PAB led to an increase in RVEF, this was reduced by PAB in the WD group (P = 0.02). (d) Invasively measured hemodynamics demonstrated prolonged relaxation time, Tau, in both HFD at baseline (P = 0.047) and with PAB (P = 0.04). *P < 0.05 vs. SD, #P < 0.05 WD-PAB vs. SD-PAB.

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  Fig. 2.. WD is associated with disproportionate RV steatosis. (a) Oil Red O stain for lipid in the RV demonstrates increased lipid droplets (red) in standard image (left) and digitally enhanced (right) in WD-fed mice. (b) Percent lipid stain in (a) is quantified and shown to be increased in the WD RV compared to the SD RV (P < 0.01). WD did not significantly augment LV lipid content. (c) Oil Red O images from RV and LV demonstrating no increase in lipid content in the WD LV. *P < 0.05 WD RV vs. WD RV.

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  Fig. 3.. Physiologic and hemodynamic effects of metformin in the context of A WD. (a) Metformin administration led to a decrease in total body weight (P = 0.005) to a level that was not different from SD-fed mice. (b) There was a similar decrease in HOMA-IR, a measure of insulin resistance (P < 0.001 WD vs. WD-metformin [WD-Met]) to levels that were similar to SD. (c) RVSP was decreased in the WD-Met group compared with the WD alone group. (d) Co-administration of metformin with WD attenuated the WD-associated changes in right ventricular hypertrophy both at baseline (P = 0.001) and with PAB (P = 0.008). *P < 0.05 WD-Met vs. WD, #P < 0.05 WD-PAB Met vs. WD-PAB.

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  Fig. 4.. Hemodynamic effects of metformin therapy. (a) Conductance catheter measurements demonstrated numerically increased RVEF in WD-Met compared to WD alone; however, no changes met statistical significance (P = 0.16). (b) Metformin therapy lead to improved diastolic filling time (tau) both at baseline (P = 0.025) and with load stress (P = 0.005). *P < 0.05 WD-Met vs. WD, #P < 0.05 WD-PAB Met vs. WD-PAB. (c) RV contractility, as assessed by dP/dTmax, was increased in PAB vs. SD; however, there was no effect of metformin. *P < 0.05 PAB vs. SD.

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  Fig. 5.. Metformin prevents lipid and ceramide accumulation in the WD RV. (a) Measurement of lipid content in the RV using Oil Red O stain on the left with digitally enhanced image on the right demonstrates reduction of RV lipid content that is quantified in (b). WD-Met is associated with normalization in RV lipid staining in both baseline conditions and load stress, PAB. (c) Immunohistochemistry for ceramide, quantified in (d), demonstrates increased ceramide content in PAB compared to unstressed conditions (P = 0.03) that is attenuated with metformin therapy WD-PAB compared to WD-PAB (P = 0.01). (e) RV CD36 expression was decreased by metformin therapy in unstressed conditions (P = 0.008). In PAB, there was a trend to decreased expression of CD36 with metformin exposure, though it did not meet statistical significance. *P < 0.05 WD-PAB vs. WD, #WD-PAB Met vs. WD-PAB.