In vivo assessment of cardiac metabolism and function in the abdominal aortic banding model of compensated cardiac hypertrophy

Abstract

Aims: Left ventricular hypertrophy is an adaptive response of the heart to chronic mechanical overload and can lead to functional deterioration and heart failure. Changes in cardiac energy metabolism are considered as key to the hypertrophic remodelling process. The concurrence of obesity and hypertrophy has been associated with contractile dysfunction, and this work therefore aimed to investigate the in vivo structural, functional, and metabolic remodelling that occurs in the hypertrophied heart in the setting of a high-fat, high-sucrose, Western diet (WD).

Methods and results: Following induction of cardiac hypertrophy through abdominal aortic banding, male Sprague Dawley rats were exposed to either a standard diet or a WD (containing 45% fat and 16% sucrose) for up to 14 weeks. Cardiac structural and functional characteristics were determined by CINE MRI, and in vivo metabolism was investigated using hyperpolarized (13)C-labelled pyruvate. Cardiac hypertrophy was observed at all time points, irrespective of dietary manipulation, with no evidence of cardiac dysfunction. Pyruvate dehydrogenase flux was unchanged in the hypertrophied animals at any time point, but increased incorporation of the (13)C label into lactate was observed by 9 weeks and maintained at 14 weeks, indicative of enhanced glycolysis.

Conclusion: Hypertrophied hearts revealed little evidence of a switch towards increased glucose oxidation but rather an uncoupling of glycolytic metabolism from glucose oxidation. This was maintained under conditions of dietary stress provided by a WD but, at this compensated phase of hypertrophy, did not result in any contractile dysfunction.

Keywords: 13C magnetic resonance spectroscopy; Cardiac hypertrophy; Dynamic nuclear polarization; Metabolic remodelling; Pyruvate dehydrogenase.

Figure 1

Cardiac hyperpolarized ¹³C signal localization is achieved via the high local sensitivity of the RF surface coil used and the high metabolic rate of the heart relative to other organs/tissues within the sensitive region of the coil (A, LV, left ventricular lumen; RV, right ventricular lumen; myo, myocardial tissue). This figure, acquired with a 3D spectral-spatial, echo planar spectroscopic imaging sequence [matrix: 32 × 32 × 12, field of view: 64 × 64 × 45.5 mm³, acquired resolution: 2 × 2 × 4 mm³, echo time (TE): 16.3 ms, repetition time (TR): 1RR interval (≈150 ms); flip angle: 17° pyruvate/61°bicarbonate], demonstrates that the pyruvate signal (B) originates primarily from the blood in the chambers of the heart, while the downstream metabolic signals, in this example bicarbonate (C), are originating from the front wall of the left ventricle.

Figure 2

Representative in vivo CINE MR images of sham and AAB hearts at 14 weeks post-surgical induction of cardiac hypertrophy during systole and diastole, (A and B) on standard chow diet, (C and D) on WD.

Figure 3

Cardiac structural parameters assessed in control and AAB animals at 4, 9, and 14 weeks post-surgical induction of cardiac hypertrophy. (A) LVM, (B) heart weight to body weight ratio, (C) end-diastolic volume, and (D) end-systolic volume. *P < 0.05 in WD groups compared with standard chow groups and ^§P < 0.05 in AAB groups compared with sham control groups. Group sizes as indicated on individual bars.

Figure 4

Functional characteristics of control and AAB hearts in vivo. (A) Ejection Fraction, (B) stroke volume, (C) cardiac output, and (D) cardiac index in sham and AAB animals at 4, 9, or 14 weeks post-surgical induction of cardiac hypertrophy, exposed to standard chow or WD. *P < 0.05 in WD groups compared with standard chow groups and ^§P < 0.05 in AAB groups compared with sham control groups. Group sizes as indicated on individual bars.

Figure 5

Representative in vivo ¹³C spectra of hearts following injection of hyperpolarized [1-¹³C] pyruvate in sham control and AAB animals at 14 weeks post-surgical induction of cardiac hypertrophy exposed to either standard chow or a WD.

Figure 6

In vivo rates of incorporation of hyperpolarized [1-¹³C]pyruvate into (A) bicarbonate (pyruvate dehydrogenase flux) and (B) lactate at 4, 9, and 14 weeks post-surgical induction of cardiac hypertrophy and exposure to standard chow or WD. *P < 0.05 in WD groups vs. standard chow and ^§P < 0.05 in AAB groups vs. respective sham controls. Group sizes as indicated on individual bars.

Figure 7

Ratio of (A) citrate, (B) glutamate, and (C) acetylcarnitine to injected hyperpolarized [2-¹³C]pyruvate at 4, 9, and 14 weeks post-surgical induction of cardiac hypertrophy and exposure to standard chow or WD. ^$P < 0.05 WD AAB group compared with chow AAB group and *P < 0.05 WD groups compared with standard chow groups. Group sizes as indicated on individual bars.

Figure 8

(A) Cardiac PDK4 protein expression and (B) cardiac TAG content at 14 weeks post-surgical induction of cardiac hypertrophy (AAB) and exposure to standard chow or WD. *P < 0.05 WD groups compared with standard chow groups. Group sizes as indicated on individual bars. X represents an internal standard on the western blot.