High fat feeding in mice is insufficient to induce cardiac dysfunction and does not exacerbate heart failure

Abstract

Preclinical studies of animals with risk factors, and how those risk factors contribute to the development of cardiovascular disease and cardiac dysfunction, are clearly needed. One such approach is to feed mice a diet rich in fat (i.e. 60%). Here, we determined whether a high fat diet was sufficient to induce cardiac dysfunction in mice. We subjected mice to two different high fat diets (lard or milk as fat source) and followed them for over six months and found no significant decrement in cardiac function (via echocardiography), despite robust adiposity and impaired glucose disposal. We next determined whether antecedent and concomitant exposure to high fat diet (lard) altered the murine heart's response to infarct-induced heart failure; high fat feeding during, or before and during, heart failure did not significantly exacerbate cardiac dysfunction. Given the lack of a robust effect on cardiac dysfunction with high fat feeding, we then examined a commonly used mouse model of overt diabetes, hyperglycemia, and obesity (db/db mice). db/db mice (or STZ treated wild-type mice) subjected to pressure overload exhibited no significant exacerbation of cardiac dysfunction; however, ischemia-reperfusion injury significantly depressed cardiac function in db/db mice compared to their non-diabetic littermates. Thus, we were able to document a negative influence of a risk factor in a relevant cardiovascular disease model; however, this did not involve exposure to a high fat diet. High fat diet, obesity, or hyperglycemia does not necessarily induce cardiac dysfunction in mice. Although many investigators use such diabetes/obesity models to understand cardiac defects related to risk factors, this study, along with those from several other groups, serves as a cautionary note regarding the use of murine models of diabetes and obesity in the context of heart failure.

Figure 1. Long-term high fat diet results in altered cardiac function.

(A) Glucose tolerance test (GTT) (B) GTT A.U.C. in LFD, HFDM and HFDL treated mice. (C) Dexascan images of LFD, HFDM and HFDL fed mice. (D,E) Quantitative dexascan analysis of total lean mass and fat mass expressed as percent of total body weight. (F) M-mode from conscious echocardiogram utilizing the Vevo 770 imaging system. (G-H) Diastolic diameter was not significantly altered in either HFD group. Systolic diameter was significantly decreased in HFDL compared to LFD. (I) Fractional shortening was significantly elevated in HFDL vs. LFD and HFDL vs. HFDM. Data are presented as mean ± S.E., *p< 0.05 vs. LFD, #p< 0.05 vs. HFDM.

Figure 2. High fat diet post-infarction has no affect on cardiac function.

(A) Long axis m-mode utilizing the Vevo 770 imaging system. (B-D) Ejection fraction, diastolic volume, and systolic volume were calculated using Simpson’s method. (E) Left Ventricular pressure was assessed via Millar catheter. (F) Cardiac contractility as accessed by the minimum and maximum rate of pressure change (dP/dt). (G) The rate of relaxation (Tau) and (H) the cardiac work remained unchanged between the groups. Results are expressed as means ± S.E., *, p< 0.05.

Figure 3. A high fat diet preceding and continued after infarction has no affect on cardiac function.

(A) Long axis m-mode utilizing the Vevo 770 imaging system. (B-D) Ejection fraction, diastolic volume, and systolic volume were calculated using Simpson’s method. (E) Left Ventricular pressure was assessed via Millar catheter. (F) Cardiac contractility as accessed by the minimum and maximum rate of pressure change (dP/dt). (G) The rate of relaxation (Tau) and (H) the cardiac work remained unchanged between the groups. Results are expressed as means ± S.E., *, p< 0.05.

Figure 4. High fat diet does not affect mitochondrial bioenergetics but desensitizes mitochondria to Ca²⁺ induced permeability transition.

Mitochondrial bioenergetics were assessed in HFD and ND mice, (A) no significant difference in the individual mitochondrial respiration states or (B) respiratory control ratios were observed. Mitochondrial swelling following administration of a single bolus of Ca²⁺ was assayed and revealed (C) that HFD resulted in a significant increase in mitochondrial Ca²⁺ buffering capacity when compared to ND. Results are expressed as means ± S.E., *, p< 0.05.

Figure 5. Ischemia reperfusion injury is exacerbated by hyperglycemia and obesity.

db/db or heterozygous nondiabetic littermates were subjected to ischemia/reperfusion injury. (A) Long axis m-mode utilizing the Vevo 770 imaging system. (B-D) Fractional shortening was significantly decreased while diastolic diameter and systolic diameter were significantly increased in the IR+db/db group compared to the IR+nondiabetic group. Results are expressed as means ± S.E., *, p< 0.05.

Figure 6. Hyperglycemia does not affect progression of pressure overload induced cardiac dysfunction.

(A) Long axis m-mode utilizing the Vevo 770 imaging system. (B-D) Ejection fraction was not significantly changed from control groups through eight weeks of TAC. Diastolic and systolic volumes did not differ between the TAC+db/db and the TAC+WT groups. Results are expressed as means ± S.E., *, p< 0.05.

Figure 7. Pressure overload is not exacerbated by hypoinsulinemia via streptozotocin treatment.

(A) Fractional shortening remained unchanged between the groups through eight weeks of TAC. (B-C) Diastolic and systolic diameters were assessed via long axis m-mode echocardiography on the Acuson Sequoia C512 imaging system. No change between TAC+Buffer and TAC+STZ treated mice was observed through eight weeks of TAC. Results are expressed as means ± S.E., *, p< 0.05.