In conventional MRI, image generation is dependent on the net magnetisation signal of proton spins derived from a small excess of nuclear spins aligned with an external magnetic field in the bore of an MRI scanner. The spin alignment can be described as either ‘spin up’ or ‘spin down’ (i.e. with or against the direction of the applied magnetic field) or as a high- or low-energy state. Image generation uses radiofrequency energy applied to the area of interest to transition these spins between low- and high-energy states.
The sample net polarisation, defined as the excess of spins in the low-energy state, is the key factor in determining the available signal. Factors that influence the degree of sample polarisation include the external magnetic field strength, sample temperature and the gyromagnetic ratio of the nucleus. For protons at 1.5 T and biological temperatures, only a tiny fraction (0.00099%) of the available nuclei contribute to typical MR signals.
As such, just increasing the MR field strength does not significantly alter the intrinsically limited signal-to-noise ratio. Fortunately, protons are in very high abundance in biological tissue, which helps to mitigate this problem. However, when other nuclei are the focus of the MR study, then alternative methods need to be deployed to enhance their signal.
Hyperpolarisation with Dynamic Nuclear Polarisation
Different methods of hyperpolarisation exist to increase MR signals of nuclei with low abundance in bodily tissue. Dynamic nuclear polarisation (DNP) is the key process used for hyperpolarised 13C MRI scanning. This involves mixing radicals (a source of free electrons) with the molecule of interest, specifically the MR active stable isotope 13C.1 This is of particular interest to cardiovascular studies because carbon molecules form the backbone of many metabolites and biological processes. This sample is cryo-cooled to around 1 K in a strong magnetic field (usually 3–5 T) (Figure 1).
Applying microwave energy at a specific frequency, this unified polarisation can be transferred to the 13C nucleus, thereby increasing the signal more than 10,000-fold.2 The hyperpolarised sample then undergoes dissolution and heating to biological temperatures prior to administration, typically using heated water. For human studies, pre-administration quality checks for residual electron paramagnetic agent (EPA), temperature and pH are performed to ensure patient safety. Additional endotoxin and toxicity tests are performed post-injection. This dissolution process causes rapid decay of the hyperpolarisation at an exponential rate dependent upon the T1 time of the molecule (typically 40–60 seconds). As such, the hyperpolarised molecule needs to be administered as soon as possible (ideally under 90 seconds) once prepared. Subsequent data acquisition has to be performed very rapidly using MR spectroscopy imaging, chemical shift encoding methods, or metabolite-specific imaging in which each metabolite of interest is excited and imaged alternatively using spectrally and spatially selective radiofrequency pulses.3,4 The hyperpolarised 13C nuclei can then be tracked through the metabolic enzymatic processes, in which each resulting product metabolite has a distinct chemical shift; an advantage over clinically available PET using fluorodeoxyglucose F18 (FDG), which assesses tracer uptake rather than in vivo real-time metabolism.5
Currently, the most carefully studied and clinically promising molecule for metabolic and other cardiovascular applications with hyperpolarised 13C MRI is 13C-labelled pyruvate, which is the focus of this review, although a strong pipeline of molecules in preclinical development will also be translated to human use in the near future.6
Hyperpolarised 13C Pyruvate
Cardiac work requires a significant amount of chemical energy in the form of adenosine triphosphate (ATP) generated in mitochondria. Fuel for this process is usually derived from free fatty acid beta-oxidation (70–90% of cardiac ATP synthesis). The remainder is through pyruvate oxidation and a small contribution from glycolysis. The source of fuel used is dependent on the fed or fasted state, increased workload or hypoxia, with the healthy heart able to have an adaptive metabolic flexibility based on the prevailing metabolic demands (Box 1). Pyruvate is a three-carbon chain and is the end product of glycolysis, linking glucose uptake to the tricarboxylic acid (TCA) cycle (Figure 2). Given its central role in energy generation, tracking 13C-labelled pyruvate may help to assess enzymatic flux in cardiac metabolism. Hyperpolarised MRI can be performed with a 13C label at either the first or second carbon position of pyruvate. This labelled pyruvate can be converted into lactate, alanine or bicarbonate. The conversion to bicarbonate occurs via pyruvate dehydrogenase (PDH), a critical enzyme central to metabolic pathways. Thus, hyperpolarised MRI is able to uniquely assess PDH flux by measuring the rate of 13C label incorporation from [1-13C]pyruvate into [13C]bicarbonate.7,8
Box 1: Fuel Sources for Cardiac Metabolism in Health and Disease
Healthy heart:
- Free fatty acids are the predominant fuel source in cardiac metabolism
- Others include glucose, lactate, ketone bodies, amino acids
- Healthy heart has metabolic flexibility depending on physiological availability
Ischaemia:
- Metabolic shift to increased lactate production
Cardiometabolic diseases:
- Increased reliance on free fatty acids for oxidative energy production
Heart failure:
- Metabolic shift to glycolysis and increased oxidation of ketone bodies
Although [1-13C]pyruvate remains the most widely used probe due to its central role in glycolysis and oxidative phosphorylation, additional hyperpolarised substrates have been developed (Table 1). Examples include [2-13C]pyruvate, which enables downstream tracking of Krebs’ cycle intermediates, [1-13C]acetate, assessing oxidative metabolism, and 13C-urea as a perfusion marker due to its non-metabolised nature.9–11
Current studies have demonstrated an excellent safety profile for the use of hyperpolarised pyruvate and it has met regulatory approval for human use from international regulatory bodies.12,13 While there are limitations to hyperpolarisation as detailed later in the review, hyperpolarised MRI has the potential to be integrated into a conventional cardiovascular MRI (CMR) workflow albeit with logistical caveats.
Initial work by Golman et al. using rats demonstrated the use of DNP to generate hyperpolarised 13C probes with images acquired by MRI.14 Since this seminal study there have been steady advances in preclinical studies in hyperpolarised 13C MRI to test the feasibility and safety of new hyperpolarised probes and to assess their applications in specific disease models. Initial human studies with hyperpolarised pyruvate were initially done in prostate cancer.15 While the number of institutions with hyperpolarised MRI is still limited, there has been a rapid growth of studies over the last decade.16 Much of the research interest has been focused on oncology, where hyperpolarised MRI may have a role in identifying occult malignancies, detecting and grading metastatic disease and assessing treatment response.17 Clinical studies in cardiovascular disease using hyperpolarised MRI remain in their infancy. Since the first published 13C images of the human heart nearly 10 years ago, there has been a steady stream of cardiovascular hyperpolarised 13C MRI publications, accounting for 14% of research studies in this field.16,18 While the clinical indications for hyperpolarised 13C cardiac MRI are not yet clear, it may have particular strengths in the assessment of ischaemic heart disease, particularly for evaluating ischaemia, perfusion and viability.19 In addition, there may be a role for this in the assessment of patients with heart failure or inflammatory conditions.19
Ischaemic Heart Disease
Acute MI
Clinically available imaging tools for myocardial ischaemia use surrogate markers of coronary flow or perfusion. This is in contrast to hyperpolarised 13C MRI, which is able to directly visualise areas of ischaemia, which might help to more precisely diagnose ischaemia at the molecular level, and, as such, potentially target revascularisation at an earlier stage. During ischaemia there is a metabolic shift to anaerobic glycolysis from oxidative pathways. As such, hyperpolarised 13C MRI may be used to detect alterations in lactate and bicarbonate and a drop in pH in ischaemic areas of the heart.20 Initial preclinical work showed the feasibility of cardiac metabolic imaging during an ischaemic reperfusion model in pigs injected with [1-13C]pyruvate.21 The left circumflex artery was occluded for 15 or 45 minutes, followed by 2 hours of reperfusion. After 15 minutes of occlusion (no infarction), there was a reduction (25–44%) in bicarbonate signal level in the affected area compared with normal myocardium, with normal alanine signal levels.21 Following 45 minutes (infarction), the bicarbonate signal was near absent and there was a reduction (27–51%) in the alanine signal.21 Moreover, there was raised lactate and reduced bicarbonate in a model of ex vivo left anterior descending (LAD) infarction and in the anterior and anterolateral segments in a left coronary ischaemia reperfusion rat model.22 This was corroborated by studies in pigs that demonstrated a reduction in bicarbonate and lactate signals following 10 minutes of mid-LAD occlusion. Immediately on reperfusion the lactate signal increased while bicarbonate remained depressed after 5 minutes following reperfusion.20
Perfusion Imaging
Metabolically inert hyperpolarised probes may enable assessment of perfusion. HP001 (bis-1,1-(hydroxymethyl)-[1-13C]cyclopropane-d8), a non-endogenous hyperpolarised substrate, enabled the investigation of tumour perfusion in rats using MRI.23 An adenosine stress model in rats demonstrated potential utility of hyperpolarised 13C urea, which appears to have the benefit of reduced artefacts and avoidance of signal contamination with bright signal from the blood pool.11 Furthermore, first-pass myocardial perfusion using hyperpolarised 13C urea in pigs demonstrated very good agreement in direct comparison with 1H gadolinium measurements.24
The first human studies demonstrated the feasibility of the adenosine stress in the healthy human heart together with hyperpolarised [1-13C]pyruvate CMR.25 That study of six healthy volunteers showed that increased heart rate was associated with an increased pyruvate oxidation during low to moderate cardiac stress.25 These promising early findings could pave the way for larger sample sizes and studies in patients with coronary artery disease.
Viability Assessment
Another utility of hyperpolarised 13C MRI is to assess and complement the current methodologies to determine viable myocardium, a common clinical question to determine whether patients may benefit from revascularisation. In a rat model of acute infarction induced by in vivo LAD ligation there was a significant increase in lactate with a corresponding reduction in bicarbonate.26 In chronic infarction 4 weeks later, there was a significant reduction in both lactate and bicarbonate signals, with the complete absence of both metabolites demonstrating non-viable tissue.26 In a porcine model of ischaemia, 60 minutes of LAD occlusion resulted in heterogeneous infarcts.27 In animals with transmural non-viable apical infarcts based on late gadolinium enhancement (LGE), myocardium remained metabolically inactive 1 week post-infarct with an absence of detectable bicarbonate and no restoration of wall motion.27 Conversely, wall motion returned when bicarbonate signal normalised after reperfusion in those with no infarct LGE, and wall motion recovery correlated positively with bicarbonate.27 Whether this can be translated into humans and whether there is additional benefit over standard CMR LGE quantification is not yet known.
The first human case reports to use hyperpolarised 13C MRI in acute MI were in a patient presenting with a non-ST-elevation MI and another with a late ST-elevation MI (Figure 3).28 Apps et al. showed that non-viable segments with transmural infarction had absent 13C bicarbonate and lactate signals while viable segments following subendocardial infarction showed preserved 13C bicarbonate and lactate signals, delineating the real-time metabolic differences with respect to viability and supplementing information derived from conventional LGE imaging.28
Comparison with PET Imaging in Ischaemic Heart Disease
Perfusion assessment using hyperpolarised probes may have utility in investigating patients with balanced ischaemia, which may affect interpretation of perfusion in other imaging modalities such as single-photon emission CT, and perfusion imaging with radioactive tracers. Currently, clinically available imaging modalities including PET with rubidium-82 (Rb-82) can overcome this by assessing myocardial blood flow. One unique potential advantage of using hyperpolarised MRI for perfusion assessment is the simultaneous assessment of metabolism and perfusion in a single scan, as demonstrated in a rat model using co-polarised bolus of hyperpolarised [1-13C]pyruvate and 13C-urea.29 This may have clinical importance to ascertain the extent of myocardial damage by simultaneously assessing both blood flow (perfusion) and viability (intact metabolism) following acute infarction when myocardial oedema can overestimate the infarct size based on LGE assessment alone. More studies are required to ascertain whether lower-grade ischaemia can be detected with hyperpolarised 13C MRI.
While PET may be used for viability assessment, hyperpolarised [1-13C]pyruvate MRI could potentially replace PET given the additional information derived from real-time metabolic measurements.30 While both hyperpolarised 13C MRI and PET involve logistical challenges that come at a relatively high cost, MRI has an advantage in that it does not require radioactive material. The achievable in-plane spatial resolution for hyperpolarised 13C MRI is around 6 mm for pyruvate and 12 mm for its products, which is comparable to PET (4–5 mm).31 However, the out-of-plane resolution of hyperpolarised 13C MRI is still coarse, which may limit the interpretation of images, although advances to improve this are ongoing.32 Last, analysis of PET images is relatively more straightforward using standardised uptake value or parametric maps compared with hyperpolarised 13C MRI, which requires either multiple area-under-the-curve (AUC) metabolite maps or pharmacokinetic (PK) models.33
Heart Failure
Alterations in cardiac energy metabolism in heart failure have been extensively studied and demonstrate a reduction in the phosphocreatine reserve pool for ATP generation using 31P magnetic resonance spectroscopy (MRS).34 There is a switch from beta oxidation of fatty acids to carbohydrates such as glucose, which are more oxygen efficient. However, PDH flux is depressed, thought in part to be due to insulin resistance in heart failure.35
In a pig model of heart failure with reduced ejection fraction induced by rapid pacing, hyperpolarised 13C MRI showed early changes, including impairment of Krebs’ cycle metabolism with a reduction in label incorporation into [13C]glutamate and an initial preservation of pyruvate oxidation.7 However, with prolonged rapid pacing leading to systolic dysfunction there were further reductions in the glutamate/pyruvate ratio and impairment of PDH flux.7 In a rat model of post-MI heart failure, using a hyperpolarised [2-13C]pyruvate probe, impaired Krebs’ cycle activity in vivo preceded a reduction in PDH flux, the latter correlating with left ventricular ejection fraction (LVEF).36
Cardiometabolic disease, specifically obesity and diabetes, is associated with the development of heart failure with preserved ejection fraction (HFpEF).37 There may be a role for hyperpolarised 13C MRI to investigate the changes in cardiac energy metabolism in these conditions.38 This is supported by studies demonstrating reductions in PDH flux in rodent models of diabetes.7 Moreover, inhibition of PDH kinases and thus activation of PDH with dicholoracetate showed improvements in diastolic function.39 In a rat model of obesity with mild left ventricular (LV) hypertrophy and diastolic dysfunction, hyperpolarised 13C MRI demonstrated that obesity was associated with reduced myocardial PDH flux.40 Moreover, there was altered cardiac TCA cycle metabolism (using [2-13C]pyruvate) with a significant increase in [1-13C]citrate and [5-15C]glutamate.40 In contrast, there were no significant changes in the normalised rate of label incorporation into [1-13C]acetylcarnitine.40 Interestingly, subsequent caloric restriction and liraglutide treatment led to normalisation of these metabolic changes with an improvement in cardiac diastolic function assessed by echocardiography.40
With changes in fuel usage in heart failure, hyperpolarised 13C MRI may also be used to investigate fatty acid oxidation and ketone metabolism using alternative probes such as [1-13C]β-hydroxybutyrate and [1-13C]acetoacetate.41 Patients with heart failure have elevated ketone bodies in the plasma, and myocardial ketone usage as a fuel source for ATP generation is preserved.42 Clinical studies in heart failure patients have demonstrated improved haemodynamics with exogenous ketone body treatment.43 In a preclinical model, five pigs underwent β-3-hydroxybutyrate (β-3-OHB) infusion during a hyperinsulinaemic euglycaemic clamp.44 There were significant increases in cardiac output and hyperpolarised [2-13C]pyruvate MRI demonstrated a shift towards an increase in lactate and decreased levels of acetyl-carnitine and glutamate during β-3-OHB infusion.44 The authors concluded that ketone bodies could improve cardiac function by providing an energy-efficient substrate that is preferentially used.
The first case-control study to assess changes in cardiac energy metabolism compared participants with (n=13) and without (n=12) type 2 diabetes.45 Participants underwent 31P and 1H MRS while a subset (n=5 diabetes patients, n=5 controls) underwent hyperpolarised 13C MRI. In participants with diabetes, PDH flux was significantly reduced compared with controls. In addition, there was a significant increase in PDH flux observed after an oral glucose challenge (p<0.001). Following that study, a cross-sectional study used hyperpolarised 13C MRI to assess the metabolic changes in heart failure (HF) patients, comprising a mix of patients with ischaemic cardiomyopathy (n=6) and dilated cardiomyopathy (n=6), compared with healthy controls (n=6).46 Metabolic signals were normalised to total carbon signal (TC). In patients, LVEF correlated with lactate/bicarbonate and lactate/TC. In patients with severe LV dysfunction (LVEF<30%), lactate/TC was increased and bicarbonate/TC reduced.46 There were significant positive correlations in circumferential strain with lactate/bicarbonate and lactate/TC, and significant negative correlations with bicarbonate/TC.46 Moreover, in patients with ischaemic heart disease there was a strong correlation between baseline metabolite ratios (lactate/bicarbonate, lactate/TC and bicarbonate/TC).46
In a study assessing metabolic changes with cardiotoxicity, nine women with breast cancer requiring neoadjuvant doxorubicin (cumulative 240 mg/m2) underwent hyperpolarised MRI with [1-13C]pyruvate.47 After four cycles of chemotherapy there was a significant decrease in bicarbonate/TC with no change in lactate or alanine signals.47 There were small but significant changes in haemoglobin, high-sensitivity troponin and peak LV global longitudinal strain on echocardiography.47 The authors postulated that these findings may be consistent with subtle mitochondrial injury, although this was not proven.47
These initial clinical studies demonstrate how hyperpolarised 13C MRI may be used to non-invasively metabolically phenotype patients with heart failure. With the increasing availability and numerous trials investigating effective therapies in cardiometabolic diseases and HFpEF, hyperpolarised 13C MRI could be used to investigate the mechanistic effects of these novel or repurposed drugs.48 A small Phase IIa open-label trial of 21 participants with cardiometabolic syndrome investigated the short-term (4–8 weeks) effects of ninerafaxstat, a novel mitotrope agent enhancing PDH flux and modulating myocardial substrate usage, on myocardial energetics and cardiac energy metabolism. At baseline, participants had impaired phosphocreatine (PCr)/ATP, myocardial steatosis and LV diastolic dysfunction.48 Following treatment with ninerafaxstat, there was an improvement in myocardial energetics by 32% (p<0.01), reduced myocardial triglyceride content by 34% (p=0.03) and a trend towards improved PDH flux (mean 45%, p=0.08).48 Moreover, diastolic function was significantly improved as determined by peak diastolic strain rate and peak LV filling rate.48 This initial study demonstrates the utility of incorporating hyperpolarised 13C MRI in clinical trials. In addition, hyperpolarised 13C MRI may also be used to identify potential metabolic changes that may be targets for the discovery and development of novel therapeutics.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is inherently associated with alterations in cardiac energy metabolism. Sarcomere function in HCM is abnormal, with an increase in the energy cost of force production and microvascular disease, leading to an energy-deficient state. At the cellular level, most mutations resulting in HCM increase total force production and ATP usage, and thus higher myocardial energy demand.49 Inefficient energy usage for force generation may lead to energetic stress and adverse cardiac remodelling.49–52 In HCM, there are alterations in lipid metabolism and mitochondrial oxidative phosphorylation.53 Interestingly, mitochondrial DNA mutations altering mitochondria structure and function often develop an HCM phenotype in preclinical models and in patients, suggesting that primary energetic alterations can also lead to HCM pathology.54–56 Specifically, abnormal myocardial hypertrophy is linked to a significant shift of energy use to glucose oxidation rather than from free fatty acids. Patients with HCM have altered myocardial energetics, demonstrated by a significantly reduced PCr/ATP ratio by 31P MRS.49 A multi-omics approach using septal myomectomy samples in HCM patients has identified derangement in major metabolic pathways compared with normal controls.57
At present there has been only one study that assessed HCM using hyperpolarised MRI, confined to a small number of patients whose phenotypes were not well defined.58 In that study of five HCM patients, there were metabolic changes suggestive of glycolysis–glucose oxidation uncoupling and high glucose oxidation although the metabolic profiles were heterogeneous across the group.58 Regional quantification using the American Heart Association 16-segment model with hyperpolarised [1-13C]pyruvate MRI has been demonstrated, which could be used in patients with HCM.59 Metabolic profiling with hyperpolarised [1-13C]pyruvate MRI may help to diagnose HCM in cases of borderline phenotypes. The advent of hyperpolarised [1-13C]pyruvate MRI may be used to investigate changes in myocardial energy metabolism related to novel HCM treatments such as the cardiac myosin inhibitor, mavacamten, as well as to identify potential targets for drug development.60
Inflammation in the Heart
Compared with other clinically available imaging modalities, a unique strength of cardiac MRI is the assessment of fibrosis and oedema in the myocardium, often seen in diseases such as myocarditis, sarcoidosis, reperfusion injury and so on. Hyperpolarised 13C MRI may add to this by distinguishing myocardium (highly oxidative with energy generation through PDH) and activated immune cells (predominantly glycolytic). This was demonstrated in preclinical models in rats and pigs, in which there was a significant increase in lactate signals after experimental MI.61 These findings were supported by an almost doubling of hyperpolarised lactate label flux rates in in vitro macrophage-like cell suspensions, showing macrophage activation and polarisation with lipopolysaccharide.61
The release of troponin or LDH can indicate myocardial necrosis following MI; however, changes in these biomarkers do not always indicate myocardial injury. Hyperpolarised 13C MRI is able to detect an exclusive marker of myocardial necrosis using the metabolic tracer hyperpolarised [1,4-13C2]fumarate, which is converted to [1,4-13C2]malate following the release of intracellular fumarase into the extracellular space.62 Miller et al. showed that the novel tracer hyperpolarised [1,4-13C2]fumarate demonstrated an increase of [1,4-13C2]malate 82-fold compared with controls 1 day after infarction and remained increased 31-fold 1 week after infarct in rat hearts.63 These findings highlight a possible role for hyperpolarised [1,4-13C2]fumarate to distinguish the extent of myocardial necrosis in infarction compared with hyperpolarised [1-13C]pyruvate, which detects changes associated with the monocyte–macrophage inflammatory response.61
Limitations of Hyperpolarised 13C MRI
The major limitation of hyperpolarised 13C MRI is the duration required to prepare the hyperpolarised probe followed by its rapid decay after dissolution (approximately 3 hours). Given this, facilities and additional equipment (attached with a high cost) necessary for hyperpolarisation need to be adjacent to the MRI scanner. Pyruvate injection is an investigational MRI contrast agent and can be administered in humans only if researchers hold an Investigational New Drug exemption from the Food and Drug Administration (FDA) in the US or have received approval from the relevant local regulatory body.16 Hyperpolarised pyruvate and hyperpolarised xenon (for lung perfusion imaging) are currently the only probes with FDA approval.31
Given the significant time and manpower required to prepare the hyperpolarised probe, clinical adoption will require progress towards easier and faster probe preparation that meets regulatory approval. Furthermore, training and expertise are required for quality control prior to treatment. Thus, technical challenges remain and are current obstacles to its widespread adoption.
Clinical research using hyperpolarised 13C MRI remains in its early phase, and, hence, more evidence is needed to ascertain how this technology can be applied in clinical practice and what benefits exist over and above current imaging methods. Current research output is generated from a small number of institutions that perform hyperpolarised 13C MRI research in cardiovascular diseases (Table 2). While limitations exist at different levels of implementation of this technology, advances in research continue to be made, ranging from the development of novel hyperpolarised probes to MRI sequences.31 Parahydrogen-induced polarisation hyperpolarisation (PHIP) is an alternative method to generate probes in a more controllable, more cost-efficient, faster and technically less demanding manner than DNP. However, PHIP typically requires organic solvents and a catalyst that must be removed before treatment. Therefore, studies are focused on producing fully biocompatible aqueous solutions.31
One approach is parahydrogen-induced polarisation hyperpolarisation by side-arm hydrogenation (PHIP-SAH), which produces hyperpolarised pyruvate samples much more rapidly (within 85 seconds in an automated process) than DNP.64 Signal amplification by reversible exchange (SABRE) is an alternative PHIP method.65 SABRE does not require a precursor and is expected to be cheaper with fewer impurities.31 However, compared with PHIP-SAP, SABRE provides lower polarisation and at lower concentrations, which may represent a challenge in scaling for clinical use.31 The Hyperpolarised 13C MRI Consensus Group, as well as the ISMRM Hyperpolarised Media MR and Hyperpolarised Methods and Equipment study groups, have published guidance on hyperpolarised 13C MRI methodology and there are open access educational resources to support development of this growing field.16,66 Agreement in best practice will assist in ensuring a uniform methodology that will provide benefits such as permitting data comparison across sites and performing multi-centre studies.66
Conclusion
There is promising potential for hyperpolarised 13C MRI to be used as an imaging tool to investigate cardiac energy metabolism across a wide spectrum of cardiovascular diseases. Research in this developing technology remains at an early stage, particularly with regard to human studies, and is still validating findings that may have clinical potential. Advances in hyperpolarisation techniques with PHIP methods to facilitate clinical workflow and the use of artificial intelligence to assist in image acquisition and analysis will help make inroads into clinical adoption. This novel technology may enable metabolic profiling to supplement currently available non-invasive imaging, thereby helping to refine the diagnosis and management of cardiovascular conditions. The role that hyperpolarised 13C MRI has to play in the clinical setting is still to be determined, and larger, ideally multi-centre studies are now needed. Indications in the assessment of ischaemic heart disease and heart failure appear to be the strongest. A potential role could be in facilitating decision-making for revascularisation in situations in which current imaging modalities are limited, for example in the assessment of viability following acute MI. The opportunity to assess real-time in vivo metabolic changes in the myocardium with hyperpolarised 13C MRI will no doubt provide new insights into cardiovascular disease pathophysiology and may even identify novel metabolic targets for pharmacotherapies.
Clinical Perspective
- Hyperpolarised 13C MRI enhances magnetic resonance signal over 10,000-fold by increasing nuclear spin alignment via dynamic nuclear polarisation (DNP), enabling real-time, non-invasive assessment of metabolic processes such as glycolysis and oxidative phosphorylation.
- This technique enables direct evaluation of cardiac metabolic flux, offering novel insights into conditions such as ischaemic heart disease, heart failure, cardiometabolic disorders, hypertrophic cardiomyopathy and myocardial inflammation, identifying changes in lactate and bicarbonate metabolism that correlate with disease state.
- Although there are emerging early clinical data and a strong safety profile, hyperpolarised 13C MRI remains technically demanding and costly, with limited accessibility. Progress in probe development, faster polarisation methods, and regulatory approval are critical for broader clinical adoption.