Usefulness of Magnetic Resonance Spectroscopy for Clarifying the Real-Time Cardiac Metabolic Status In Vivo
論文ID: CJ-25-0427
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論文ID: CJ-25-0427
Alterations in myocardial metabolism are implicated in the pathophysiology of cardiac disorders and may contribute to the development of cardiac disease.1 Magnetic resonance spectroscopy (MRS) techniques are available as a powerful tool to non-invasively explore various aspects of cardiac metabolism in vivo, showing real-time and serial snapshots of the pathophysiology of cardiac disorders, which could potentially serve as early clinical markers for cardiac diseases. In this issue of the Journal, Tu et al.2 examine the myocardial lipid content using 1H (proton)-MRS in an experimental model of anthracycline-induced cardiotoxicity. Here, the usefulness of 31P (phosphorus)-MRS and 1H-MRS for clarifying the real-time cardiac metabolic status in vivo will be discussed.
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To date, the 31P-MRS technique has provided insights into myocardial energetics, principally through the assessment of the phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio.3 The creatine kinase (CK) enzyme system plays a crucial role in the transfer (mediated by the mitochondrial CK) and reversible transfer (mediated by the cytosolic CK) of high-energy phosphates. Creatine is phosphorylated into PCr, which acts as an energy buffer to maintain the ATP concentration in near-equilibrium. In this context, the cardiac PCr/ATP ratio is an established marker of myocardial energy metabolism, and is reduced in patients with heart failure, regardless of the underlying etiology.4,5 That finding is consistent with the energy-starvation hypothesis that the failing heart can be characterized as an “engine out of fuel.”6 Hansch et al. reported a reduced PCr/ATP ratio in patients with dilated cardiomyopathy (DCM), which correlated with left ventricular ejection fraction (LVEF).4 Dass et al.5 likewise demonstrated that in hypertrophic cardiomyopathy (HCM), the resting PCr/ATP ratio was lower than in healthy controls. In their same study, the ratio declined further during leg exercise in HCM patients but remained unchanged in controls. Moreover, PCr/ATP values measured both at rest and during stress correlated with diastolic function.
The 1H-MRS technique can quantify the myocardial triglyceride (TG) content.1 Essentially, the main source of energy for cardiomyocytes is primarily derived from the β-oxidation of fatty acids in mitochondria. In the failing heart, a mismatch between uptake and oxidation of fatty acids can result in cellular lipid accumulation, enhanced reactive oxygen species (ROS) generation and cytotoxicity. In contrast to PCr/ATP ratio, however, myocardial TG content may be related to a specific cause of disease rather than the severity of cardiac dysfunction.7 For instance, myocardial lipid levels are elevated in obese individuals and those with type 2 diabetes.8 Increased lipid content has been observed specifically in the border zone of acute myocardial infarction.9 Lipid content is decreased in HCM, but there is a very wide variation in DCM.7 Although rare, hereditary disorders in which fatty acid catabolism is primarily impaired can produce massive myocardial TG deposition. Hirano et al. reported that a patient homozygous for a nonsense mutation in the adipose triglyceride lipase gene developed TG deposit cardiomyovasculopathy, characterized by diffuse TG infiltration of the myocardium, coronary arteries and skeletal muscle, and ultimately underwent heart transplantation.10 This unique phenotype highlights that 1H-MRS-based TG quantification may prove valuable for diagnosing and monitoring primary lipid-storage cardiomyopathies.11
According to Tu et al., myocardial lipid levels detected by 1H-MRS increased 6 weeks after anthracycline administration, which preceded the decline in LVEF observed at 8 weeks in their male rabbit model.2 The pathogenesis of anthracycline-induced cardiotoxicity is as follows. Topoisomerase 2B (TOP2B), highly expressed in cardiomyocytes, forms the TOP2B-anthracycline-DNA complex, which causes DNA damage leading to cell apoptosis. The tumor suppressor protein p53, a pivotal enzyme for activating DNA repair proteins, can cause mitochondrial dysfunction and metabolic failure, resulting in enhanced ROS generation and ultimately cell death.12 It is thus reasonable that alterations in lipid metabolism followed by lipid accumulation in the myocardium would serve as an early clinical marker for anthracycline-induced cardiotoxicity.2
These findings have important implications for clinical practice, especially in cardio-oncology. MRS may allow for early risk stratification based on metabolic changes. Patients exhibiting significant deteriorations in the PCr/ATP ratio or surges in myocardial TG content after only 1–2 chemotherapy cycles may benefit from the early initiation of cardioprotective strategies, such as dexrazoxane, β-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, as recommended by contemporary cardio-oncology guidelines.13 Conversely, it might be enough for patients with a stable cardiac metabolic status to receive less intensive treatment. Individualized monitoring of cardiac metabolic status could help refine treatment decisions and avoid unnecessary treatment.
Serving as a non-invasive “biochemical biopsy” of the heart, MRS could visualize the otherwise invisible metabolic signs of stress – from lipid accumulation to energy depletion – that precede and accompany myocardial dysfunction. Evidence from preclinical models, including the work by Tu et al.,2 makes a compelling case that 1H-MRS can detect early metabolic derangements before mechanistic myocardial dysfunction occurs. Meanwhile, 31P-MRS offers a gauge of the heart’s high-energy phosphate status that correlates with functional capacity and outcomes in heart failure. These modalities can be used in combination to grasp the timeline of cardiotoxic injury: from early response, through progression, to recovery. For clinicians, real-time metabolic monitoring opens new frontiers in preventive cardio-oncology, which enables intervention based on metabolic risk markers rather than lagging indicators such as LVEF. For researchers, MRS deepens mechanistic insight by linking molecular pathology with organ-level physiology (Figure).
MRS enables non-invasive “biochemical biopsy” of the heart. 1H-MRS detects myocardial TG accumulation, while 31P-MRS measures the high-energy phosphate status via the PCr/ATP ratio. Together, these modalities enable early detection of cardiac metabolic stress and may support personalized intervention strategies. 1H-MRS, proton magnetic resonance spectroscopy; 31P-MRS, phosphorus magnetic resonance spectroscopy; ATP, adenosine triphosphate; HF, heart failure; LVEF, left ventricular ejection fraction; MRS, magnetic resonance spectroscopy; PCr, phosphocreatine; TG, triglyceride.
To fully leverage the clinical utility of cardiac MRS, several practical challenges must be overcome. First, scan efficiency needs improvement. Protocols enabling single-breath-hold acquisition and motion-resolved reconstruction would facilitate integration into routine cardiac MRI workflows. Second, robust normative reference ranges for PCr/ATP and TG content should be established, accounting for age, sex and magnetic field strength. Third, automated quantification tools (ideally using artificial intelligence) could reduce operator dependence and minimize misinterpretations from blood or epicardial fat contamination. Finally, integrating MRS-derived metabolic markers with strain imaging and circulating biomarkers may improve early diagnostic sensitivity and specificity, especially in patients undergoing cardiotoxic therapies.14
In conclusion, MRS is useful for clarifying the real-time cardiac metabolic status in vivo. This technique is expected to be a powerful tool for understanding the pathogenesis/pathophysiology and detecting early markers for cardiac abnormalities, as well as determining the appropriate therapy and evaluating the therapeutic effect for an individual with cardiac metabolic alterations.
The figure was created using BioRender.com.
None.
H.M. is a member of the Circulation Journal’s Editorial Team.
