Noninvasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized 13C MRI

Abstract

Rationale: The recent development of hyperpolarized ¹³C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time.

Objective: By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart.

Methods and results: Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (³¹P-magnetic resonance spectroscopy), and lipid content (¹H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-¹³C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1-¹³C]pyruvate via PDH (pyruvate dehydrogenase, [¹³C]bicarbonate), lactate dehydrogenase ([1-¹³C]lactate), and alanine transaminase ([1-¹³C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P=0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (P<0.001). As is characteristic of diabetes mellitus, impaired myocardial energetics, myocardial lipid content, and diastolic function were also demonstrated in the wider study cohort.

Conclusions: This work represents the first demonstration of the ability of hyperpolarized ¹³C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

Keywords: diabetes mellitus; diabetic cardiomyopathy; hyperpolarized magnetic resonance spectroscopy; magnetic resonance imaging; metabolism; pyruvate dehydrogenase.

Figure 1.

Outline of our typical study visit. The fasting stipulation in our study restricted our recruitment to what can be considered a fairly mild phenotype of diabetes mellitus—only those patients receiving oral medication. The total study visit was under 3 hours; however, each hyperpolarized magnetic resonance spectroscopy (MRS) scan took only a few minutes, meaning its addition to the normal length of routine magnetic resonance protocols would be insignificant. CKD indicates chronic kidney disease; CMR, cardiac magnetic resonance; eGFR, estimated glomerular filtration rate; and HbA1c, glycated hemoglobin.

Figure 2.

Example data collected during our study from a recruited control (top row) and a subject with type 2 diabetes mellitus (bottom row). In characterizing our recruits both structurally (cardiac magnetic resonance [CMR]/Echo) and metabolically (³¹P magnetic resonance spectroscopy [MRS], ¹H MRS, hyperpolarized ¹³C MRS), we collate the most comprehensive study of the diabetic cardiac phenotype to date. LV indicates left ventricular; and RV, right ventricular.

Figure 3.

Representative examples of hyperpolarized magnetic resonance spectra from both a healthy control and a subject with type 2 diabetes mellitus in both the fasted and fed states, with ¹³C containing downstream metabolites labeled. The [¹³C]bicarbonate resonance is visibly reduced in the subject with type 2 diabetes mellitus with increases seen during feeding in both controls and subjects with type 2 diabetes mellitus. Time courses of the normalized signal amplitudes of downstream ¹³C-labeled metabolic products of administered [1-¹³C]pyruvate (shown in blue), in both a control and a subject with type 2 diabetes mellitus are also shown.

Figure 4.

Plots of metabolic flux data for each metabolic product of administered [1-¹³C]pyruvate. Flux through PDH (pyruvate dehydrogenase; bicarbonate, A) is reduced in the subjects with type 2 diabetes mellitus (P=0.013), with increases seen during feeding (P<0.001, E). Levels of [1-¹³C]lactate were significantly higher in the hearts of people with type 2 diabetes mellitus (P<0.001, B) with no change observed on feeding (F). The ratio of bicarbonate and lactate was significantly lower in the subjects with type 2 diabetes mellitus (P<0.001, C) and was elevated by feeding (P<0.001, G). No significant differences in [1-¹³C]alanine were seen across all injections (D and H). ‘x’ indicates the data point excluded as an outlier. †P<0.05 in subjects with type 2 diabetes mellitus vs controls and *P<0.05 in fasted subjects vs fed.