Imaging the cardiac diet

Unremitting physiological stress initiates a series of maladaptive changes in cardiac gene expression, calcium cycling, and metabolism that are thought to contribute to the transition from a normal, functionally compensated heart to failing cardiomyopathy. Clinically, this is observed with hypertension, aortic and mitral valvular disease, and after ischaemic, viral, or toxic myocardial injury. Because the transition to functional decompensation can be rather abrupt, after years of apparent compensation, management of pre-heart failure is often tantamount to managing a horse that has already left the stable. Thus, there is a critical need for clinical testing to predict measureable functional decompensation in the form of a practical non-invasive test that can measure the underlying molecular and biochemical abnormalities that drive the progression to overt heart failure. Schroeder et al. have now described improvements in hyperpolarized magnetice resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) that potentially address this need. The heart is an omnivore with a voracious appetite that consumes . 6 kg of ATP each day. Although cardiac tissue can utilize multiple substrates for ATP production, free fatty acids (FFAs) are preferred over glucose or amino acids under physiological conditions. In failing hearts, substrate utilization reverts to a fetal pattern, characterized by a shift from FFAs to glucose as the preferred metabolic substrate. Failing cardiomyocytes therefore rely heavily on efficient glycolysis, and changes in glycolytic pathways have been associated with worsening heart failure. Therapies intended to restore glycolytic dysfunction in heart failure are currently under investigation in clinical trials. Despite decades of intensive research, there are still no evidence-based therapies that target metabolic dysfunction in heart failure. Perhaps the most daunting challenge for metabolic drug development is lack of tools to study cardiac metabolism in patients. Metabolic analysis of plasma lacks cardiac specificity, and analysis of isolated cardiac fibres is specific, but not applicable to intervention trials. Positron emission tomography (PET) is currently the gold standard for metabolic analysis of heart failure, but is limited in its ability to link metabolism to function, to distinguish between tracers and metabolites, and by its use of ionizing radiation. MRS has shown promise for metabolic studies but, until recently, lacked sensitivity. A potential breakthrough is the development of dynamic nuclear polarization (DNP), which increases the signal intensity of tracers . 10 000-fold; preliminary studies indicate that DNP can greatly improve cardiac MRS. In the current issue of the European Journal of Heart Failure, Schroeder et al. tested whether the increased sensitivity afforded by hyperpolarized MRI/MRS could detect changes in glycolysis before actual heart failure development in a porcine model of pacing-induced dilated cardiomyopathy. The authors used a comprehensive protocol, which combined conventional cardiac MRI and MRS, and utilized three different tracers validated for cardiac applications. [1-C]Pyruvate was used to monitor the conversion of pyruvate into bicarbonate, reflecting the flux through the pyruvate dehydrogenase complex (PDC), an early Krebs cycle-independent step in glycolysis. [2-C]Pyruvate was used to interrogate the glycolytic flux through the Krebs cycle, measured as the flux from pyruvate into glutamate. P tracers were used to quantify the cardiac energy reserve. MRI/MRS was performed at baseline and at weekly intervals until the pigs developed signs of heart failure, after which they were killed. Strikingly, hyperpolarized MRI/MS detected decreased [5-C] glutamate (and glutamate/pyruvate ratio) within 2 weeks of cardiac pacing. In the same pigs, there was almost no reduction in LVEF or increase in LV diastolic volume, the measures of LV function and remodelling that define dilated cardiomyopathy, seen after 4–6 weeks. Despite progressive reductions of Krebs cycle activity as cardiac function deteriorated, pyruvate flux through the PDC was maintained until physical signs of heart failure ensued, at which time it declined precipitously. The reductions in PDC activity were associated with increased activity of PDC kinase 4, a negative regulator of the PDC. Thus, hyperpolarized magnetic resonance was capable of tracking changes in pyruvate metabolism over time. The authors should be applauded for their careful and detailed work, which clearly shows that MRI/MRS holds a great potential for non-invasive, real-time imaging of cardiac metabolism. If the promise holds true, MRI/MRS could have multiple potential