, Jianfeng Wang 1,2, Xiaoliang Shao 1,2, Feifei Zhang 1,2,*
1 Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China
2 Institute of Clinical Translation of Nuclear Medicine and Molecular Imaging, Soochow University, 213003 Changzhou, Jiangsu, China
Abstract
Heart failure with preserved ejection fraction (HFpEF) represents a major phenotype of heart failure and accounts for over 50% of clinical cases. The complex pathophysiological mechanism involved in HFpEF promotes diagnostic difficulties and limited treatment options, posing a significant challenge in modern cardiology. Conventional imaging methods have significant limitations in comprehensively evaluating the heterogeneous etiologies and key pathological mechanisms of HFpEF. Radionuclide myocardial imaging, through the application of targeted radioactive tracers, enables in vivo, non-invasive quantitative assessment of multiple pathological and physiological processes such as myocardial perfusion, energy metabolism, sympathetic nervous activity, inflammatory responses, and fibrotic progression. Moreover, this technology offers a transformative approach to the precise diagnosis, molecular phenotyping, risk stratification, therapeutic monitoring, and prognostic assessment of HFpEF. Therefore, this review systematically summarizes the latest progress in radionuclide myocardial imaging techniques in diagnosing and treating HFpEF, with a particular focus on analyzing the unique clinical value of this technology in identifying specific etiologies (such as cardiac amyloidosis, cardiac sarcoidosis, and coronary microvascular dysfunction) and elucidating pathological mechanisms (including metabolic remodeling, inflammatory, fibrosis, and alterations in sympathetic innervation). Furthermore, we discuss the future directions of this imaging modality, including the development of novel molecular probes, integration with multimodal imaging techniques, and the application of artificial intelligence-assisted analysis. These innovations are expected to facilitate a paradigm shift from symptom-oriented management to mechanism-targeted therapy, offering new perspectives for the precise classification and clinical management of HFpEF.
Keywords
- heart failure with preserved ejection fraction
- radionuclide imaging
- positron emission tomography
- single-photon emission computed tomography
- molecular imaging
Heart failure with preserved ejection fraction (HFpEF) accounts for more than
50% of heart failure cases. Its incidence has been continuously rising along
with an aging population and the growing prevalence of metabolic diseases such as
diabetes and obesity [1, 2]. Unlike heart failure with reduced ejection fraction
(HFrEF), HFpEF is characterized by preserved left ventricular ejection fraction
(LVEF)
Cardiovascular imaging techniques are crucial in the diagnosis and etiology of HFpEF. Echocardiography and cardiac magnetic resonance (CMR) are widely utilized imaging modalities for assessing structural and functional abnormalities, including left ventricular diastolic dysfunction and myocardial fibrosis. However, conventional imaging modalities are limited in their ability to assess key mechanisms such as microvascular dysfunction, myocardial metabolic abnormalities, and sympathetic dysregulation, making it challenging to fully reveal the underlying causes and key pathophysiological mechanisms of HFpEF. Radionuclide myocardial imaging, a functional molecular imaging technique, enables multidimensional evaluation of myocardial perfusion, metabolism, sympathetic nerve activity, inflammation, and fibrosis through radioactive tracer technology. It not only helps to identify specific etiologies (e.g., cardiac amyloidosis, sarcoidosis, coronary microvascular dysfunction), but also can deeply analyze key pathophysiological mechanisms such as myocardial metabolic abnormalities, inflammation, sympathetic nerve imbalance, and fibrosis [7]. This provides a unique perspective for the precise phenotyping and individualized management of HFpEF.
This review aims to comprehensively explore the clinical application of radionuclide myocardial imaging in HFpEF, with a focus on its unique value in identifying specific etiologies such as cardiac amyloidosis, cardiac sarcoidosis, and coronary microvascular disease and elucidating pathophysiological mechanisms including inflammation, fibrosis, metabolic remodeling, sympathetic nerve function, and cardiac function. It also offers novel insights for the precise diagnosis of HFpEF, optimization of clinical management, improvement of patient prognosis, and future research directions, thereby promoting the shift from traditional symptom-based management to mechanism-targeted therapeutic strategies.
Radionuclide myocardial imaging mainly relies on positron emission tomography (PET) and single photon emission computed tomography (SPECT) [7]. Due to its broad availability and relatively low cost, SPECT is widely utilized in routine clinical practice for evaluating myocardial perfusion, sympathetic nerve activity, and cardiac amyloidosis. PET, with its outstanding spatial resolution and precise quantitative analysis capabilities, is particularly adept at accurately assessing myocardial metabolic status, microvascular function, and inflammatory responses. It is valuable in the diagnosis, classification, mechanistic analysis, prognosis evaluation, and treatment monitoring of HFpEF.
In clinical practice, various radioactive tracers provide powerful tools for the
assessment of different pathophysiological processes. The applicable scope, usage
precautions and limitations of common tracers are detailed in Table 1 (Ref. [8, 9, 10, 11, 12, 13]). In the evaluation of myocardial perfusion, commonly used
tracers include 99mtechnetium-methoxy isobutyl isonitrile (99mTc-MIBI)
and 201thallium (201Tl) for SPECT, as well as 13N-ammonia,
15O-water and 82rubidium (82Rb) for PET. The latter allows for
quantitative measurement of myocardial blood flow (MBF) and myocardial blood flow
reserve (MFR). PET is considered the gold standard for noninvasively assessing
regional MBF—and is especially valuable in detecting coronary microvascular
dysfunction (CMD) in HFpEF patients. In metabolic imaging,
18F-fluorodeoxyglucose (18F-FDG) and Iodine-123
| Radiotracer | Clinical application | Radiation dose | Notes for attention | Limitations |
| 18F-FDG [11] | Evaluation of inflammation; | 3.8–7.2 mSv | Maintain strict glycemic control (target |
Low specificity for etiology; |
| Cardiac sarcoidosis diagnosis; | Fast for 6–12 hours pre-procedure; avoid glucose-containing IV fluids; | Susceptible to blood sugar fluctuations | ||
| Ischemic memory; | Pre-treat with high-fat/low-carb diet; | |||
| Myocardial metabolic evaluation | Contraindications during pregnancy | |||
| 99mTc-MIBI [12] | SPECT-based perfusion imaging; | 7–9 mSv | Safe and widely used; | Semi-quantitative; |
| Detection of CMD; | good availability | Limited MBF assessment | ||
| Ischemia and Infarction | ||||
| 99mTc-PYP [13] | Diagnosis of ATTR-CA | Image acquisition 3 hours post-injection; | Not suitable for AL-CA; | |
| Perform semi-quantitative analysis with blood pool imaging; | Requires serum exclusion | |||
| Dose adjustment required for severe renal impairment patients | ||||
| 123I-MIBG [10] | Cardiac Sympathetic Function Assessment; | 2.5–3.5 mSv | Discontinue tricyclic antidepressants 6 weeks prior; | Influenced by comorbidities (diabetes, CKD); |
| Neuroendocrine Tumors | Thyroid blockade (potassium iodide 120 mg daily |
Inter-individual variability | ||
| Monitor heart rate variability post-injection; | ||||
| Avoid use in acute phase of acute coronary syndrome | ||||
| 68Ga-FAPI [9] | Imaging myocardial fibrosis and remodeling | 3–5 mSv | Low background uptake; | Lacks large-scale validation |
| Good image contrast | ||||
| 68Ga-DOTATATE [8] | Myocardial Metastasis of Neuroendocrine Tumors; | 4.5–5.5 mSv | Discontinue somatostatin analogues 24–72 hours prior; | Clinical use in HFpEF is still exploratory; |
| Targeted Molecular Imaging of M1 Macrophage-Associated Inflammation | Evaluate renal function (use with caution if GFR |
Quantitative analysis complexity; | ||
| Thyroid blockade requires potassium iodide pre-treatment | Limited to certain inflammatory types |
HFpEF, heart failure with preserved ejection fraction; 18F-FDG, 18Fluorine fluorodeoxyglucose; IV, intravenous; 99mTc-MIBI, 99mtechnetium methoxy isobutyl isonitrile; SPECT, single-photon emission computed tomography; CMD, coronary microvascular dysfunction; MBF, myocardial blood flow; 99mTc-PYP, 99mtechnetium pyrophosphate; ATTR-CA, transthyretin cardiac amyloidosis; AL-CA, light-chain (AL) cardiac amyloidosis; 123I-MIBG, 123I-metaiodobenzylguanidine; CKD, chronic kidney disease; 68Ga-FAPI, 68Gallium fibroblast activation protein inhibitor; 68Ga-DOTATATE, 68Gallium-labeled DOTA-(Tyr3)-Octreotate; GFR, glomerular filtration rate.
| Imaging modality | Targeted etiologies/mechanisms | Advantages | Limitations | Cost & availability |
| Echocardiography [1, 15] | Structural assessment; | Economical; | Limited tissue characterization; | Low cost; |
| Wall motion-diastolic dysfunction; | Real-time, bedside; | Operator-dependent; | Widely available | |
| Amyloidosis (strain pattern) | Global and regional function; | Cannot directly detect inflammation/fibrosis | ||
| No radiation; | ||||
| Safe for all populations | ||||
| CMR [14, 16] | Myocardial fibrosis; | High spatial resolution; | Contraindicated in some patients (devices); | Moderate cost; |
| Infiltrative disease (amyloid/sarcoid); | Tissue characterization (LGE, T1/T2/ECV); | Contraindicated in severe renal dysfunction; | Moderate availability | |
| Edema/inflammation- Ischemia/perfusion; | Quantitative perfusion; | Long scan time; | ||
| CMD (perfusion reserve) | No ionizing radiation | Poor availability in some regions | ||
| SPECT [5, 7] | Myocardial perfusion (ischemia/CAD); | High specificity; | Limited spatial resolution; | Moderate cost; |
| ATTR amyloidosis (99mTc-PYP/DPD); | Capable of prognostic evaluation; | Semi-quantitative; | Very accessible | |
| Sympathetic innervation (123I-MIBG); | Widespread clinical use | Radiation exposure; | ||
| Inflammation (99mTc-HMPAO) | Less sensitive than PET for flow/metabolism; | |||
| Moderate radiation (5–10 mSv); | ||||
| Avoid in pregnancy; | ||||
| Caution in thyroid disease (MIBG) | ||||
| PET [7, 14] | Myocardial perfusion & MBF/MFR (CAD, CMD); | Highest quantitative accuracy; | Moderate radiation (4–10 mSv); | High cost; |
| Inflammation (18F-FDG, 68Ga-DOTATATE); | Gold standard for CMD; | Contraindicated in pregnancy; | Limited in many centers | |
| Amyloidosis (18F-florbetapir, 11C-PIB); | Early inflammation detection; | Requires fasting for 18F-FDG PET | ||
| Sympathetic innervation (11C-HED); | Absolute MBF and MFR; | |||
| Fibrosis (68Ga-FAPI) | Molecular specificity |
HFpEF, heart failure with preserved ejection fraction; CMR, cardiac magnetic resonance; SPECT, single photon emission computed tomography; PET, positron emission tomography; CMD, coronary microvascular dysfunction; CAD, coronary artery disease; ATTR-CA, transthyretin cardiac amyloidosis; 99mTc-PYP/DPD/HMDP, 99mTc-pyrophosphate/99mTc-3,3-diphosphono-1,2-propanediacetic acid/99mTc-hydroxymethylene diphosphonate; 123I-MIBG, 123I-metaiodobenzylguanidine; 99mTc-HMPAO, 99mTc hexamethylpropyleneamine oxime; MBF, myocardial blood flow; MFR, myocardial flow reserve; 11C-PIB, 11C-Pittsburgh compound-B; 18F-FDG, 18F-fluorodeoxyglucose; MIBI, methoxy isobutyl isonitrile; LGE, late gadolinium enhancement; ECV, extracellular volume; 68Ga-FAPI, 68Gallium fibroblast activation protein inhibitor; H/M, heart-to-mediastinum; WR, washout rate; 11C-HED, 11C-hydroxyephedrine; 68Ga-DOTATATE, 68Gallium-labeled DOTA-(Tyr3)-Octreotate.
Cardiac amyloidosis (CA) is a form of infiltrative cardiomyopathy caused by the deposition of misfolded amyloid proteins in the myocardium. The two predominant subtypes are light-chain cardiac amyloidosis (AL-CA) and ATTR-CA [17]. Recent studies have revealed that approximately 13% of patients diagnosed with HFpEF may actually have undiagnosed CA [6]. Given the significant differences in treatment strategies for AL-CA and ATTR-CA, early and accurate differentiation between these subtypes is of paramount clinical importance [18]. Although myocardial biopsy with histopathological examination is the gold standard for diagnosing CA, its invasiveness and procedural risks limit widespread clinical use. Echocardiography may detect characteristic changes such as increased ventricular wall thickness, but these findings often present only in the advanced stages of the disease [19]. CMR can demonstrate characteristic late gadolinium enhancement suggestive of amyloid deposition, yet lacks specificity for distinguishing CA subtypes. In contrast, radionuclide myocardial imaging provides a non-invasive and highly specific alternative for diagnosis and subtype differentiation. They have been recommended by international guidelines as a first-line diagnostic tool [20, 21].
Several bone scintigraphy tracers [22], such as 99mTc-PYP,
99mTc-3,3-diphosphono-1,2-propanediacetic acid (99mTc-DPD), and
99mTc-hydroxymethylene diphosphonate (99mTc-HMDP), selectively bind to
microcalcification proteins associated with ATTR-CA and exhibit high diagnostic
specificity. They have been widely used for non-invasive screening and diagnosis
of ATTR-CA. Diagnostic criteria include myocardial radiotracer uptake
The 2023 European Society of Cardiology (ESC) Guidelines on Cardiomyopathies
[21] state that DPD/PYP/HMDP SPECT myocardial imaging is the gold standard for
diagnosing ATTR-CA and it may obviate the need for myocardial biopsy.
Additionally, novel amyloid-targeted PET tracers such as 11C-Pittsburgh
compound-B (11C-PIB), 18F-florbetapir, 18F-flutemetamol, and
18F-florbetaben, specifically bind to the
Radionuclide myocardial imaging has become a key tool for the diagnosis, classification and disease monitoring of CA. Among them, SPECT bone imaging tracers have become the first-line diagnostic tool for ATTR-CA, while PET provides more possibilities for the precise differentiation of AL-CA and ATTR-CA. In the future, with the development of new PET tracers and the advancement of quantitative analysis techniques, radionuclide myocardial imaging is expected to further enhance the early diagnosis of coronary artery disease (CAD), facilitate pathological classification, and play a more significant role in individualized treatment and prognosis assessment.
Cardiac sarcoidosis (CS) is an infiltrative cardiomyopathy characterized by non-caseating granulomatous inflammation of the myocardium. If left undiagnosed or untreated, it may progress to irreversible myocardial fibrosis, leading to life-threatening arrhythmias, treatment-resistant heart failure, or sudden cardiac death. Early initiation of immunosuppressive therapy during the active inflammatory phase is crucial. In patients with poor responses to immunosuppressive and heart failure medications, implantation of a left ventricular assist device (LVAD) or heart transplantation should be considered. Therefore, early and accurate diagnosis of CS and assessment of disease activity are of great significance for timely and precise treatment and reduction of adverse cardiovascular events.
Multiple expert statements recommend 18F-FDG PET imaging to confirm the diagnosis in patients with suspected CS [34, 35]. The clinical utility of 18F-FDG PET includes [36]: (1) Early diagnosis: 18F-FDG PET can detect myocardial inflammation before the structural or functional changes, offering an earlier diagnostic window compared to CMR. A meta-analysis reported a sensitivity of 84% and specificity of 83% for 18F-FDG PET in diagnosing CS [37]. Whole-body PET imaging is also useful for identifying extracardiac sarcoidosis [38], with a sensitivity of 83% and specificity of 100% when extracardiac uptake is included. (2) Assessment of disease activity and staging: Positive 18F-FDG uptake reflects active inflammation. When combined with resting perfusion imaging, PET can distinguish disease stages: normal perfusion with increased 18F-FDG uptake suggests early inflammation; reduced perfusion with elevated uptake implies both necrosis and inflammation; matched defects in perfusion and FDG uptake imply myocardial scarring. (3) Therapy guidance and monitoring: If 18F-FDG PET is positive, immunosuppressive therapy is required, and 18F-FDG PET scans can be repeated at 3, 6 and 12 months after treatment to evaluate the therapeutic effect and guide further treatment plans. After immunosuppressive therapy, if myocardial 18F-FDG imaging remains positive, it is one of the indications for pacemaker implantation. (4) Prognostication: 18F-FDG positivity correlates with major adverse cardiovascular events (MACE) in CS.
PET/MRI holds great promise in the comprehensive assessment of CS. 18F-FDG PET detects early inflammatory infiltration, while MRI can precisely evaluate multiple parameters such as myocardial edema and myocardial fibrosis. The two complement each other and accurately reflect the pathological changes of CS. One case study shows that a 66-year-old male patient presented with chest pain, the biopsy was confirmed as cardiac sarcoidosis. CMR revealed late gadolinium enhancement (LGE) and high T2-weighted signal in the anterior ventricular septum area. At the same time, this area showed enhanced FDG uptake, with the maximum standardized uptake value being 6.4. After 4 months of steroid treatment, the LGE and T2W signal intensities significantly decreased, and FDG uptake completely disappeared. This patient was determined to have a good therapeutic response, and no MACE occurred during the follow-up period [39]. However, 18F-FDG also has some limitations. Physiological myocardial uptake of 18F-FDG can alter image interpretation. Due to the physiological uptake of 18F-FDG in normal myocardium, multiple methods such as a low-carbohydrate and high-fat diet, long-term fasting, and intravenous injection of heparin before imaging [40] to reduce the uptake of 18F-FDG in normal myocardium can improve the diagnostic accuracy [41].
Several studies have confirmed that 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic-1-acid-Nal3-octreotide (68Ga-DOTANOC, a somatostatin receptor imaging agent) and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT, a thymidine analogue imaging agent) have shown high accuracy in the diagnosis of CS [42, 43]. In addition, choline analogues imaging agents (such as 11C-choline and 18F-fluorocholine) and 11C-methionine have shown potential application in the diagnosis of extracardiac sarcoidosis [44, 45]. However, no current research has confirmed its application in the diagnosis of CS and further clinical research is still needed for verification.
CAD has been confirmed as one of the main pathogenic factors of HFpEF [46]. In China’s largest autopsy-based study of elderly individuals, 68.2% of HFpEF patients had coexisting CAD, and 18.2% showed evidence of chronic myocardial ischemia, providing direct pathological support for the involvement of coronary microcirculation disorders in the pathogenesis of HFpEF [47]. Notably, the clinical misdiagnosis rate of CAD in HFpEF patients reached 63.3%, and the missed diagnosis rate of myocardial infarction was over 50%, highlighting the necessity of accurately assessing both coronary macrovascular and microvascular function [47]. Both epicardial coronary artery obstruction and microvascular dysfunction can lead to myocardial ischemia.
Radionuclide myocardial perfusion imaging (MPI) is currently a widely used, evidence-based, and the most reliable non-invasive imaging for evaluating myocardial blood flow. It effectively identifies the location, extent, and severity of ischemia or infarction [48], with a diagnostic sensitivity of 82–91% and specificity of 70–90% for CAD [49]. Stress-rest MPI plays an important role in diagnosis, risk stratification and prognosis assessment of CAD, and a normal stress MPI has excellent negative predictive value for MACE [50]. In addition, radionuclide fatty acid metabolism imaging (such as 123I-BMIPP) [51] and glucose metabolism imaging (such as 18F-FDG PET) [52] use the principle of “ischemic memory” to detect recent ischemic events, even after perfusion has normalized. Research [53] shows that CMD is an established independent risk factor for HFpEF and a key pathological mechanism underlying diastolic dysfunction, yet it is undetectable by conventional coronary angiography.
SPECT and PET myocardial perfusion imaging are valuable tools for evaluating
CMD. A coronary flow reserve (CFR)
Based on the above evidence, radionuclide myocardial imaging has multiple clinical values in the management of HFpEF patients with CAD: (1) early identification of high-risk CAD patients; (2) guiding the formulation of individualized treatment strategies; (3) objectively assessing treatment effects; (4) precisely predicting disease prognosis. These advantages make it an important tool for improving the management of HFpEF patients.
As shown in Table 3 (Ref. [24, 25, 66, 67, 68, 69, 70, 71, 72, 73, 74]), the efficacy comparisons of PET, SPECT, CMR, and echocardiography in diagnosing specific causes are as follows.
| Etiology/Imaging modality | Modality | Tracer/Technique | Sensitivity (%) | Specificity (%) |
| ATTR-CA | SPECT [24, 25, 66] | 99mTc-PYP/DPD/HMDP | 91 |
87 |
| PET [67] | 18F-florbetapir/11C-PIB | 80 |
85 | |
| Echocardiography [68] | Apical sparing strain for ATTR | 97% | 90% | |
| CS | PET [69] | 18F-FDG | 81% | 82% |
| CMR [70] | T2, LGE | 76 |
76 | |
| CAD | SPECT [71] | 99mTc-MIBI/Tetrofosmin | 82 |
|
| PET [72, 73] | 13N-ammonia/82Rb | 90 |
85 | |
| CMD | CMR [74] | stress CMR perfusion | 41% | 83% |
| PET [73] | MBF/MFR analysis | 100% | 75% |
HFpEF, heart failure with preserved ejection fraction; ATTR-CA, transthyretin cardiac amyloidosis; CS, cardiac sarcoidosis; CAD, coronary artery disease; CMD, coronary microvascular dysfunction; SPECT, single photon emission computed tomography; PET, positron emission tomography; CMR, cardiac magnetic resonance; 99mTc-PYP/DPD/HMDP, 99mTc-pyrophosphate/99mTc-3,3-diphosphono-1,2-propanediacetic acid/99mTc-hydroxymethylene diphosphonate; 11C-PIB, 11C-Pittsburgh compound-B; 18F-FDG, 18F-fluorodeoxyglucose; 99mTc-MIBI, 99mtechnetium-methoxy isobutyl isonitrile; MBF, myocardial blood flow; MFR, myocardial flow reserve; LGE, late gadolinium enhancement.
Inflammatory activation is a key mechanism in the development and progression of
HFpEF. Risk factors such as overweight/obesity (particularly epicardial fat
accumulation), hypertension, diabetes and chronic obstructive pulmonary disease
may induce systemic inflammation, promoting ventricular remodeling and diastolic
dysfunction via complex signaling pathways [75]. Accurate assessment of
myocardial inflammation is therefore essential for implementing targeted
therapies. Currently, clinical evaluation primarily relies on circulating
biomarkers such as high-sensitivity C-reactive protein (hs-CRP), erythrocyte
sedimentation rate, interleukin (IL)-1
SPECT can assess myocardial inflammation related to HFpEF by labeling white
blood cells or inflammatory factors [7, 14, 78]. For example, 99mTc
hexamethylpropyleneamine oxime (99mTc-HMPAO) leukocyte imaging detects
inflammatory cell infiltration and quantifies inflammatory burden, though its
spatial resolution is suboptimal. 67Ga-citrate imaging is applicable for
chronic inflammation assessment, but its specificity is limited. In contrast, PET
enables more precise evaluation by targeting activated inflammatory cells (such
as macrophages) and their surface receptors [79]. Common PET tracers include: (1)
18F-FDG. A classic tracer for imaging myocardial inflammation, with uptake
levels closely reflecting inflammatory activity [7]. Post-acute myocardial
infarction (AMI), elevated 18F-FDG SUVmax reflects localized inflammatory
response [80], and the extent of left ventricular uptake predicts subsequent
remodeling and functional deterioration [81]. However, physiological myocardial
uptake and stringent dietary protocols limit its utility. (2) 68Ga-DOTATATE.
A specific imaging tracer for M1 macrophages, 68Ga-DOTATATE PET allows for
sensitive detection of myocardial injury and inflammation without the need for
dietary preparation, as normal myocardium shows minimal uptake [8]. (3)
68Ga-Pentixafor. Targeting the C-X-C chemokine receptor type 4 (CXCR4),
68Ga-pentixafor shows increased myocardial uptake during inflammatory states
and can predict adverse remodeling in HFpEF [82]. Werner et al. [83]
reported that the infarct-to-remote myocardium SUVmax ratio of
68Ga-pentixafor after AMI independently predicts major adverse
cardiovascular events (HR = 4.9, p
Increased epicardial adipose tissue (EAT) is associated with poor prognosis in
HFpEF and is regarded as an independent cardiometabolic risk factor [86]. Nuclear
molecular imaging, with its unique advantages, is expected to play a significant
role in precisely evaluating the inflammatory state of EAT [87]. 18F-FDG PET
has been used to quantify EAT inflammation and is independently associated with
atrial fibrillation [87, 88]. Evidence [89] also suggests “cross-talk” between
myocardial and renal inflammation post-injury, and supports a systemic
immune-metabolic interplay in HFpEF pathophysiology. Whole-body PET imaging
enables simultaneous assessment of multiple organs (e.g., brain, bone marrow,
arteries, kidneys, liver), which is critical for mapping organ-organ interactions
and systemic inflammation in HFpEF. PET/MRI fusion offers added value by
combining metabolic and anatomical information. In addition, 18F-FDG PET
imaging can detect and quantify myocardial inflammation, providing complementary
information to CMR [90]. This combined PET/MRI strategy can not only be used to
assess the inflammatory burden of HFpEF but also guide precise anti-inflammatory
treatment (such as IL-1
In summary, nuclear molecular imaging has broken through the limitations of traditional techniques, achieving dynamic visualization, quantification, and multi-target assessment of myocardial inflammation in HFpEF. This helps to screen high-risk populations with high inflammatory burden, optimize anti-inflammatory treatment strategies (such as IL-1, IL-6 inhibitors or SGLT2 inhibitors), and guide prognosis. It provides a revolutionary tool for clarifying the inflammatory mechanism, guiding targeted therapy, and improving prognosis. In the future, it is necessary to further promote the clinical transformation of new tracers and the integration of multi-modal imaging technologies to provide a “molecular microscope” for clarifying the pathogenesis of HFpEF and will further drive the diagnosis and treatment of heart failure into the era of precision medicine.
Myocardial fibrosis is a central pathological mechanism in the occurrence and development of HFpEF [1]. It impairs ventricular compliance through dual pathways of interstitial fibrosis (excessive collagen deposition) and replacement fibrosis (scar repair), leading to progressive diastolic dysfunction and significantly increasing the risk of cardiovascular death and rehospitalization for heart failure [91]. This key pathological process makes it one of the most promising therapeutic targets for HFpEF. Early and accurate identification and intervention in the fibrotic process are necessary for reversing ventricular remodeling and improving patient prognosis. Traditional diagnostic methods have obvious limitations: although endomyocardial biopsy is the gold standard [92], it is invasive and susceptible to sampling bias; CMR using LGE can only identify focal late-stage fibrosis [93]. Serum biomarkers (e.g., procollagen type I C-terminal propeptide, PICP, procollagen type I N-terminal propeptide, PINP) are limited in clinical application due to the lack of cardiac specificity. This diagnostic dilemma is being overcome by nuclear molecular imaging. By specifically targeting key molecular events of fibrosis (such as fibroblast activation, collagen synthesis and cross-linking), it has achieved a paradigm shift from “anatomical imaging” to “visualizing pathological processes”, laying the technical foundation for the era of precision medicine in HFpEF.
Fibroblast activation is a key link in the fibrotic process, and is reflective
of the early stage, activity and reversibility of fibrosis. Recently,
radiolabeled molecular probe targeting FAP, represented by 68Ga-FAPI PET,
has been able to detect the activity of myocardial fibrosis in HFpEF by binding
to FAP expressed on activated fibroblasts. Uptake in HFpEF patients is
approximately 2.1-fold higher than that in healthy controls (p
Studies involving novel tracers such as 99mTc-CBP1495 (a collagen-binding
probe) and 18F-Alfatide II (targeting
Nuclear molecular imaging has broken through the limitations of traditional imaging, achieving non-invasive, dynamic and quantitative assessment of myocardial fibrosis in HFpEF. It plays a significant role in the precise classification, treatment monitoring, and prognosis prediction of HFpEF patients. In the future, it is necessary to further promote the clinical transformation of new tracers and conduct large-scale, multi-center studies to verify their clinical application value. PET/MRI combined strategy is expected to become a new standard for the assessment of myocardial fibrosis in HFpEF. Exploring the molecular imaging strategy of fibrosis-inflammation interaction will help to formulate and optimize individualized and precise treatment strategies.
The autonomic nervous system plays an important role in regulating cardiac function, including heart rate, myocardial contractility and blood pressure. In heart failure, particularly HFpEF, sympathetic nervous system (SNS) overactivation—as well as activation of the renin–angiotensin–aldosterone system (RAAS)—contributes to adverse ventricular remodeling, increases the risk of arrhythmias, and is strongly associated with poor prognosis [99]. Nuclear imaging of cardiac sympathetic innervation has emerged as a valuable tool in clinical research and patient management [100]. The most widely used approach for evaluating cardiac sympathetic function involves imaging presynaptic nerve terminals using radiolabeled catecholamine analogues. Among them, 123I-metaiodobenzylguanidine (123I-MIBG) is a widely used SPECT imaging, while 11C-hydroxyephedrine (11C-HED) is often employed for PET imaging [100]. These radiotracers provide direct assessment of myocardial sympathetic activity and are useful for detecting autonomic dysfunction, risk stratification, prognostication, individualized therapy, and treatment monitoring in HFpEF.
Multiple studies [10, 99] have shown that 123I-MIBG imaging is more
valuable than traditional indicators such as LVEF and BNP in risk stratification
of heart failure patients and has gradually become an important tool for
assessing prognosis [101]. The heart-to-mediastinum (H/M) uptake ratio and
myocardial clearance rate are independent predictors of adverse outcomes across
various heart failure etiologies [101]. Several studies [102, 103, 104] have shown that
the H/M ratio in patients with heart failure is closely related to their poor
prognosis, regardless of whether they have HFrEF, heart failure with mid-range
ejection fraction (HFmrEF), or HFpEF. The overall sympathetic nerve function of
the heart and regional heterogeneity of cardiac innervation are also closely
related to malignant ventricular arrhythmias. A study [100] found that if there is
a region with relatively good perfusion but damaged nerves near the area of the
myocardial scar, namely “neuro-perfusion mismatch”, the patient is more prone
to arrhythmias. The PAREPET study found through 11C-HED PET inflammation
imaging that the “neuro/perfusion mismatch” area is closely related to the
occurrence of sudden cardiac death in patients with ischemic heart disease, and
is not affected by LVEF, infarction size and BNP levels [105]. In addition,
nuclear neuroimaging can assess the effects of therapeutic interventions on
sympathetic activity. A study [106] found that treatment with beta-blockers,
aldosterone antagonists, and continuous positive airway pressure (CPAP)
ventilation, significantly improves 123I-MIBG or 11C-HED uptake,
suggesting that sympathetic dysfunction is at least partially reversible. In
patients with diabetes, cardiac autonomic neuropathy (CAN) is a common and
serious complication. Among diabetic patients with heart failure, those with an
H/M ratio
Despite its clinical promise, widespread adoption of cardiac sympathetic innervation imaging faces technical challenges. 11C-labeled tracers like 11C-HED, with a half-life of only 20 minutes, must be synthesized on-site using a cyclotron, which is difficult to achieve in most medical institutions. In contrast, the 18F-labeled tracers with a half-life of up to 110 minutes, such as 18F-fluorobenzylguanidine and 18F-m-fluorobenzylguanidine, have greater practical potential [103] and hold promise for broader clinical implementation.
Although sympathetic innervation imaging has demonstrated strong prognostic value in heart failure and arrhythmias, prospective studies are still needed to demonstrate its direct impact on clinical decision-making. Consequently, this technique has not yet been incorporated into heart failure management guidelines [7]. Nevertheless, in selected high-risk or borderline patients—particularly those being considered for catheter ablation or device therapy—sympathetic imaging may serve as a valuable adjunctive tool for risk assessment and management.
Metabolic abnormalities play a key role in the pathogenesis of HFpEF. Patients with metabolic syndrome, particularly those with obesity or diabetes, frequently exhibit myocardial energy metabolism disorders, which are increasingly recognized as key contributors to impaired diastolic function. Under stress, the heart undergoes substrate shifts as a compensatory mechanism in pathological remodeling [107]. A comprehensive understanding of this metabolic reprogramming is essential not only for elucidating HFpEF pathophysiology but also for informing the development of targeted therapeutic strategies. Metabolic alterations in HFpEF are characterized by disruptions across multiple pathways, including fatty acid oxidation, glucose oxidation, glycolysis, ketone body metabolism, and branched-chain amino acid (BCAA) metabolism [108]. Nuclear molecular imaging provides a powerful tool for a comprehensive assessment of these metabolic alterations. Currently, 18F-FDG PET/CT is widely used in clinical practice to non-invasively evaluate the myocardial glucose metabolic status, especially for HFpEF patients with concomitant disorders of glucose and lipid metabolism. It can reveal changes in myocardial glucose uptake, a metabolic feature that may be closely related to diastolic dysfunction. However, 18F-FDG imaging is subject to several limitations: its uptake is influenced by insulin sensitivity, dietary status and cardiac load, resulting in poor reproducibility of the results. More importantly, it only reflects a single link of glucose metabolism and is difficult to comprehensively evaluate the myocardial metabolic network. Therefore, it is still necessary to develop more targeted and stable tracers to achieve a more accurate quantitative assessment of myocardial metabolic status.
Beyond glucose metabolism, the myocardium relies heavily on fatty acids for energy. To more comprehensively assess the myocardial metabolic status, researchers have also employed imaging agents such as 18F-fluoro-6-thia-heptadecanoic acid (18F-FTHA) and 11C-palmitate [109] to detect myocardial fatty acid uptake, thereby analyzing the balance of myocardial substrate metabolism. Some researchers [110] used 18F-FTHA and 18F-FDG as tracers and found through PET imaging that compared with normal individuals, the rate of free fatty acid uptake in the myocardium of heart failure patients decreased, while the rate of glucose uptake increased. PET/CT can assess the therapeutic effect of drugs on heart failure by comparing the myocardial metabolic changes before and after drug treatment in heart failure patients. 11C-acetate (11C-ACE) myocardial PET imaging can evaluate the aerobic metabolism of the myocardium in heart failure patients [111]. In patients with heart failure, aerobic metabolism in the myocardium increases, and the clearance rate of 11C-ACE is significantly lower than that of normal individuals. After treatment with beta-blockers, aerobic metabolism decreases and the clearance rate of 11C-ACE increases. In addition, myocardial peripheral efficiency has also become one of the indicators of concern in recent years. It can be evaluated by combining 11C-ACE PET to measure myocardial oxygen uptake and the left ventricular peripheral work estimated by the product of stroke volume and mean arterial pressure [111]. Studies [112] suggest that the efficiency of damaged myocardium is even more effective than the ejection fraction in predicting the poor prognosis of patients.
In summary, radionuclide myocardial metabolic imaging provides critical insights into the energy metabolism of the HFpEF myocardium. It shows promises for early disease detection, the response and evaluation of treatments, and precision therapy. Future research should focus on developing a multimodal metabolic assessment system to more accurately guide clinical decision-making.
Gated myocardial perfusion imaging (GMPI) is a widely used nuclear cardiology
technique in clinical practice. By using the R wave of the electrocardiogram as a
trigger, GMPI segments each cardiac cycle into 8 or 16 equal phases, allowing
sequential acquisition of myocardial images from end-systole to end-diastole
[113]. GMPI can accurately obtain the left ventricular volume-time curve, and
further calculate diastolic function parameters including peak filling rate (PFR)
and time to peak filling (TPF), as well as indices of left ventricular mechanical
dyssynchrony (LVMD), such as diastolic phase bandwidth, phase standard deviation
(PSD), and phase entropy [113]. These objective metrics allow comprehensive
assessment of both diastolic function and intraventricular synchrony. Study has
demonstrated a strong correlation between diastolic PSD and phase bandwidth
derived from GMPI phase analysis and the degree of diastolic dyssynchrony
measured by tissue Doppler imaging (TDI) [114] GMPI-derived indices exhibit
superior reproducibility, making them well-suited for longitudinal monitoring. In
HFpEF, patients frequently exhibit significant diastolic dyssynchrony despite
preserved systolic synchrony, a phenomenon linked to increased myocardial
stiffness due to fibrosis and disrupted energy metabolism [115, 116, 117]. Diastolic
dyssynchrony represents not only a hallmark pathological feature of HFpEF but
also an independent predictor of adverse outcomes [118]. It correlates with
worsening cardiac structure and function and can guide risk stratification. For
instance, post-myocardial infarction patients with a diastolic PSD
In conclusion, GMPI-derived functional parameters serve as non-invasive, reproducible imaging biomarkers for diastolic function assessment in HFpEF. These may complement clinical decision-making in risk stratification and treatment monitoring. Future prospective studies are warranted to validate their role in guiding personalized management strategies.
Radionuclide myocardial imaging has shown considerable clinical value in the diagnosis and management of HFpEF, particularly in identifying specific etiologies, uncovering key pathophysiological mechanisms, and enabling individualized risk stratification. However, its broader clinical adoption remains constrained by several challenges. High costs, limited availability of PET imaging systems, and the technical complexity of advanced tracers have restricted their widespread use, especially in resource-limited settings. In contrast, SPECT imaging using 99mTc-labeled tracers is more accessible and cost-effective, making it a practical first-line modality. A tiered diagnostic strategy—employing SPECT for initial screening (e.g., 99mTc-PYP for ATTR-CA) and reserving PET for advanced assessment in tertiary centers—is therefore recommended. Additionally, the integration of artificial intelligence (AI)—based quantitative tools may enhance diagnostic reproducibility and reduce inter-observer variability. Despite technological progress, many radionuclide imaging parameters still lack standardized diagnostic thresholds and validation in large-scale, multicenter studies. Furthermore, several promising radiotracers, such as FAPI and FLT, remain in the early stages of clinical development, necessitating further research to confirm their utility in early detection, disease monitoring, and therapeutic guidance.
Future studies should focus on several key areas. First, the integration of multimodal imaging techniques (PET/CT, PET/MR) with AI-driven image analysis will enable high-throughput, multi-dimensional assessment of HFpEF mechanisms. Second, developing more specific molecular probes targeting inflammation, fibrosis, and metabolic dysfunction may support a shift from phenotype-based to mechanism-based disease classification. Third, building comprehensive clinical models that combine nuclear imaging biomarkers with conventional tools—such as NT-proBNP, CMR, and functional scoring systems—can refine therapeutic decision-making. Fourth, evaluating the role of nuclear imaging in predicting treatment response will be crucial, particularly with the rise of SGLT2 inhibitors, anti-inflammatory agents, and anti-fibrotic therapies. Finally, advances in AI are expected to streamline image processing, optimize radiation dosing, and facilitate individualized prediction of prognosis through multiparametric modeling. In addition, enhancing patient education is of great significance in improving their acceptance and compliance with the process of radionuclide imaging. Adequate informed communication about the benefits and limitations of the examination can help increase patient compliance, especially for elderly patients or those with multiple underlying diseases.
HFpEF, often regarded as the “final frontier” in the management of heart failure, urgently demands innovative technologies to overcome persistent diagnostic and therapeutic challenges. Nuclear myocardial imaging, by virtue of its unique strengths in molecular imaging, is currently spearheading the paradigmatic transformation of the diagnosis and treatment mode of HFpEF. This technique not only transcends the constraints of traditional imaging, achieving a cognitive leap from macroscopic phenotypes to microscopic mechanisms, but also, via a multi-parameter and quantitative assessment system, furnishes crucial technical support for the precise medical practice of HFpEF. Current evidence strongly supports that nuclear imaging possesses three core values in the diagnosis and treatment of HFpEF: at the diagnostic level, it can precisely identify special etiologies and key pathological mechanisms; at the therapeutic level, it is capable of objectively assessing therapeutic effects and predicting treatment responses; at the management level, it can realize individualized prognosis assessment and the entire process management.
Looking forward to the future, with the rapid development of molecular imaging technology and the cross-integration of multiple disciplines, radionuclide myocardial imaging will realize three major transitions in the field of HFpEF: from an auxiliary diagnostic tool to a decision support system, from single-parameter evaluation to multi-omics integration, and from preclinical research to clinical translation. These transitions will profoundly affect the diagnosis and treatment strategies of HFpEF, ultimately achieving a qualitative leap from “symptomatic treatment” to “etiological treatment” and from “group-based regimens” to “individualized regimens”, providing crucial technical support for enhancing the prevention and treatment of heart failure.
SPECT, single photon emission computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging; MPI, myocardial perfusion imaging; MFR, myocardial flow reserve; MBFR, blood flow reserve; MBF, myocardial blood flow; MACE, major adverse cardiovascular events; LVEF, left ventricular ejection fraction; LVAD, left ventricular assist device; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; GMPI, Gated myocardial perfusion imaging; FAP, fibroblast activation protein; EAT, excessive epicardial adipose tissue; CXCR4, C-X-C chemokine receptor type 4; CS, cardiac sarcoidosis; CMR, cardiac magnetic resonance; CMD, coronary microvascular dysfunction; CFR, coronary flow reserve; CCR2, C-C chemokine receptor type 2; CAD, coronary artery disease; CA, cardiac amyloidosis; ATTR-CA, transthyretin cardiac amyloidosis; AMI, acute myocardial infarction; AL-CA, light chain cardiac amyloidosis; 99mTc-PYP, 99mTc-pyrophosphate; 99mTc-MIBI, 99mtechnetium-methoxy isobutyl isonitrile; 99mTc-HMDP, 99mTc-hydroxymethylene diphosphonate; 99mTc-DPD, 99mTc-3,3-diphosphono-1,2-propanediacetic acid; 68Ga-DOTATATE, 68Gallium-labeled DOTA-(Tyr3)-Octreotate; 18F-FDG, 18F-fluorodeoxyglucose; 123I-MIBG, 123I-metaiodobenzylguanidine; 123I-BMIPP, Iodine-123
FZ and YW meticulously orchestrated the conceptual framework and strategic direction for this review, subsequently conducting a thorough refinement and revision of the manuscript. YT wrote the initial draft. JW and XS provided help with editing and guidance for this manuscript. All authors contributed to editorial changes and conception in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
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This research was funded by the Applied Basic Research Project of Changzhou (CJ20241109, PI: Feifei Zhang), Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project (2022-260, PI: Feifei Zhang), Changzhou Clinical Medical Center (Nuclear Medicine) (CZZX202204), Clinical Medical Science and Technology High-end Platform and Transformation Base Construction Project of Soochow University (Characteristic Discipline)—Nuclear Medicine (PI: Yuetao Wang), the National Natural Science Foundation of China (82272031, PI: Yuetao Wang; U22A6008, PI: Sijin Li).
The authors declare no conflict of interest.
References
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