Assessment of in vivo metabolism in failing hearts using hyperpolarised 13C magnetic resonance

Introduction

Increasingly, abnormal metabolic substrate utilisation is considered a cause of heart failure (HF). Hyperpolarised ¹³C MR, a technique in which the fate of ¹³C-labelled metabolites can be followed in vivo using MR imaging or spectroscopy, has enabled non-invasive assessment of cardiac substrate utilisation.

Purpose

The aim of this study was to monitor carbohydrate metabolism alongside cardiac structure and function, throughout HF progression.

Methods

Dilated cardiomyopathy (DCM) was induced in pigs (n = 4) by rapid ventricular pacing at 188 bpm for 4-5 weeks. Pigs were examined at baseline and at weekly time points throughout DCM progression. At each time point, cine MRI was used to assess cardiac structure and function, 0.05 mmol/kg hyperpolarised ¹³C₂-pyruvate was administered intravenously and MRS was used to assess Krebs cycle-mediated ¹³C-glutamate production, and hyperpolarised ¹³C₁-pyruvate was administered to assess H¹³CO₃^- production from pyruvate dehydrogenase (PDH), and thus relative carbohydrate oxidation. A new cardiac and respiratory-gated ¹³C MRI sequence was used to image ¹³C₁-pyruvate and H¹³CO₃^-. The chemical shift-specific pulse sequence used allowed temporally resolved imaging of ¹³C₁-pyruvate and H¹³CO₃^- with 9 mm in-plane spatial resolution in multiple slices (two in these studies), all within a 23 s scan. Pigs were sacrificed after presentation of clinical symptoms or >25% increase in end diastolic volume (EDV).

Results

At baseline, pigs had an EDV of 62 ± 5 ml. The maximum ¹³C-glutamate/¹³C₂-pyruvate ratio was 4.9 ± 1.2% (Fig 1A), whereas the mean H¹³CO₃^-/¹³C₁-pyruvate ratio across the anterior myocardium was 2.0 ± 0.3% (Fig 1B). After 1 week of pacing, the ¹³C-glutamate/¹³C₂-pyruvate decreased significantly to 2.1 ± 0.8%, and was maintained at this level throughout DCM development. EDV increased linearly with pacing duration, and after 2-3 weeks of pacing was significantly elevated to 84 ± 12 ml. After 4-5 weeks of pacing (at the final time point), the ejection fraction (EF) was decreased by 40% compared with the baseline value, and the H¹³CO₃^-/¹³C₁-pyruvate was decreased to 0.8±0.2%.

Figure 1

A) Representative short-axis ¹³C images of the healthy pig heart, acquired with a surface coil. B) Comparison of parameters of structural and metabolic remodeling in the pig heart throughout the progression of DCM. *p<0.05.

Conclusions

In conclusion, metabolism of ¹³C₂-pyruvate to ¹³C-glutamate was reduced by 59% at an early stage in DCM, with no change to PDH flux. Reduced ¹³C-glutamate relative to H¹³CO₃^- production could be an early marker of disease. Carbohydrate oxidation via PDH was maintained until end-stage DCM, at which point PDH flux was reduced by 62%. With further development, metabolic imaging using hyperpolarised ¹³C MR may similarly characterize HF progression in patients.