The absence of endogenous lipid oxidation in early stage heart failure exposes limits in lipid storage and turnover

Abstract

Intramyocardial lipid handling in pressure-overload-induced heart failure remains poorly understood, and the balance between endogenous and exogenous lipid utilization for mitochondrial ATP production is essentially unknown. In this study, we determined the contribution of endogenous triacylglycerols (TAG) to mitochondrial oxidation relative to that of exogenous palmitate, glucose, and endogenous glycogen in the failing, pressure-overloaded rat heart. TAG content and turnover were also assessed to determine if lipid availability and mobility were altered. Dynamic-mode (13)C NMR was performed in intact hearts from aortic banded and sham operated Spraque-Dawley rats perfused with (13)C-labeled palmitate or glucose to assess TAG turnover rate and palmitate oxidation rate. The fractional contributions from palmitate, glucose, glycogen, and TAG to mitochondrial ATP production were determined from NMR analysis of heart extracts. TAG oxidation was not evident in HF, whereas the contribution of TAG to oxidative ATP production was significant in shams. TAG content was 39% lower in HF compared to sham, and TAG turnover rate was 60% lower in HF. During adrenergic challenge, TAG sources were again not oxidized in the HF group. In early cardiac failure, endogenous TAG oxidation was reduced in parallel to increased carbohydrate oxidation, with no change in exogenous palmitate oxidation. This finding was consistent with reduced TAG storage and mobilization. These data further elucidate the role of intermediary and lipid metabolism in the progression of LVH to failure, and contribute to emerging evidence linking the disruption of myocardial substrate use to cardiomyopathies.

Figure 1

Schematic representation of [,,,,,,,-¹³C₈] palmitate and unlabeled glucose uptake and incorporation into the triacylglycerol (TAG) and glutamate pool.

Figure 2

Rate-pressure-product (mmHg*beats/min ± S.E.) from isolated retrograde perfused rat hearts following 10 weeks aortic banded pressure-overload hypertrophy (σ HF, n=12) and sham operated healthy rats (ν sham, n=10). Data is presented for RPP at basal workloads (top) and during an adrenergic challenge (bottom). (*significant difference, p<0.05)

Figure 3

Dynamic mode ¹³C-NMR spectra obtained from an isolated perfused sham (left) and failing heart (right) oxidizing [,,,,,,,-¹³C₈] palmitate and unlabeled glucose during an adrenergic challenge (0.01 μM isoproterenol).

Figure 4

Palmitate oxidative rate normalized to RPP for shams (white bar) and heart failure (HF, black bar) at basal and high workloads (isoproterenol). Palmitate oxidation rate was well coupled to workload in the failing group relative to the shams at baseline workloads but not with the adrenergic challenge.

Figure 5

Percent contributions from each substrate to mitochondrial ATP production at basal and high workloads (isoproterenol).

Figure 6

The turnover rate of triacylglycerol pool was measured in isolated perfused shams (white bar, n=7) and failing heart (black bar, n=7), and is shown here normalized to the rate-pressure-production (turnover rate/RPP; (μmol/min/gdw)/(mmHg*beats/min) ±S.E.).