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

Abstract

Rationale: The recent development of hyperpolarized 13 C 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 ( 31 P-magnetic resonance spectroscopy), and lipid content ( 1 H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1- 13 C]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- 13 C]pyruvate via PDH (pyruvate dehydrogenase, [ 13 C]bicarbonate), lactate dehydrogenase ([1- 13 C]lactate), and alanine transaminase ([1- 13 C]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 13 C 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.

Hyperpolarized Magnetic Resonance Shows that the Anti-Ischemic Drug, Meldonium, Leads to Increased Flux Through Pyruvate Dehydrogenase In Vivo Resulting in Improved Post-Ischemic Function in the Diabetic Heart.

“…This switch in fuel utilization towards more oxygene cient glucose metabolism may account for the improved recovery post-ischemia. Given the recent demonstration of the ability of hyperpolarized magnetic resonance to study alterations in metabolism in the human heart [44,45], there is clear potential for such studies to be translated into clinical trials assessing the potential for metabolic therapies in the diabetic heart.…”

Cardiac pH-Imaging With Hyperpolarized MRI

“…The ability to image metabolism has driven its lead in the clinical translation. Recently, the first human study of cardiac disease found impaired myocardial energetics with [1-13 C]pyruvate in diabetic patients (47). Of interest to pH-imaging, they were able to detect carbon dioxide in their spectra.…”

Cardiac metabolic imaging using hyperpolarized [1-13C]lactate as a substrate

“…While the safety and feasibility of using hyperpolarized [1- 13 C]pyruvate as a tool to interrogate cellular metabolism has been demonstrated in many studies in humans (2,6,7,(13)(14)(15)(16), hyperpolarized [1-13 C]lactate represents an alternative for probing cardiac PDH flux with less perturbation of the metabolic state. At the 0.1 mmol/kg dose that has been utilized in all the human hyperpolarized [1-13 C]pyruvate studies to date, the injected substrate concentration (~2 mM after dilution by blood) would greatly exceed its endogenous blood concentration (17).…”

“…It has been demonstrated in small and large animal models that HP MRI can be used to probe changes in cardiac metabolism due to modulation in substrate availability as well as cardiac diseases (3)(4)(5). The feasibility of studying cardiac metabolism in the human heart has also been shown recently (6,7). In all the hyperpolarized metabolic imaging studies performed so far, [1- 13 C]pyruvate is the most commonly used substrate due to the high achievable polarization, long T1 relaxation time, and the important role of pyruvate in cellular metabolism.…”