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. Author manuscript; available in PMC: 2026 Apr 4.
Published in final edited form as: Heart Fail Clin. 2025 Jul;21(3):477–485. doi: 10.1016/j.hfc.2025.01.006

Radionuclide Imaging of Heart-Brain Connections

Shady Abohashem a,b, Simran S Grewal b,c, Ahmed Tawakol b,c, Michael T Osborne b,c,*
PMCID: PMC13047423  NIHMSID: NIHMS2157113  PMID: 40506159

INTRODUCTION

Recent scientific advances have led to greater attention on the heart-brain connection in disease processes involving both organs. Epidemiologic studies have identified links between maladies of the 2 systems in diverse populations. The stress response that occurs through autonomic and neurohormonal mechanisms has historically played a central role in this interplay. In addition, growing evidence supports an intimate and complex relationship between the heart and brain that involves significant crosstalk, changes in neural networks, and immune modulation to contribute to pathologic condition in both organs.1,2 Furthermore, there appears to be variation in these mechanisms between sexes.3

Although investigating the heart-brain connection has remained challenging, molecular imaging using positron emission tomography (PET) and single-photon emission tomography (SPECT) is well-positioned to provide insights into the multisystem mechanisms underlying this relationship. These techniques allow simultaneous assessment of both organ systems using a variety of radiotracers that probe tissue metabolism, perfusion, innervation, and inflammation among other processes.2,4 Furthermore, findings can be linked to imaging indices from other modalities and serologic biomarkers to generate novel observations.1 This review focuses on describing the currently available radiotracers that facilitate the evaluation of the heart-brain connection and the mechanistic insights they provide.

DISCUSSION

Clinical Associations

Acute or chronic cardiac or neurologic disease increases the risk for concurrent disease of both organs. The most common pathologic condition that impacts both organs is atherosclerosis, which manifests clinically as myocardial infarction (MI) or cerebrovascular accident, and typically stems from cardiovascular disease (CVD) risk factors, such as hypertension, diabetes, dyslipidemia, and smoking. MI associates with chronic heart failure, and both MI and heart failure are associated with impaired cognition owing to vascular and nonvascular causes.5–7 Similarly, a cerebrovascular accident enhances the risk for cognitive impairment, MI, and heart failure (even without myocardial ischemia).8,9 These relationships imply that additional connections beyond atherosclerosis contribute to disease in both organs.

In addition, the association between psychosocial stress and psychiatric disorders with adverse cardiovascular and neurologic outcomes has been increasingly recognized. People with severe psychiatric illnesses, including schizophrenia, bipolar disorder, and major depressive disorder, have 2 to 3 times higher rates of cardiovascular morbidity and mortality than the general population.10,11 Similarly, individuals under acute and chronic stress have a greater risk for cognitive dysfunction as well as adverse cardiovascular outcomes, including atherosclerotic events and Takotsubo syndrome.12–15 Accordingly, an enhanced understanding of this heart-brain interplay beyond atherosclerosis is needed to optimize patient care and develop novel therapeutic and preventative strategies.

Importantly, there is substantial evidence of variation in the heart-brain connection in men and women.3 Generally, women have a profile of a lower burden of coronary artery disease (CAD) but worse clinical outcomes compared with men. Furthermore, women more commonly suffer from a type of Takotsubo syndrome, described as broken heart syndrome, that is often triggered by negative emotions.16 Alternatively, recent findings have identified a rare type of Takotsubo syndrome, referred to as happy heart syndrome, that is more prevalent in men and is consequent to positive emotions.17 These differences suggest additional complexity in the heart-brain connection related to sex that may explain dimorphisms in disease presentation and outcomes.

Mechanisms

Multiple pathophysiologic mechanisms contribute to the complex crosstalk underlying heart-brain connections (Fig. 1). The autonomic nervous system, renin-aldosterone system, and hypothalamic-pituitary-adrenal (HPA) axis all play integral roles in governing the response to both physiologic injury and psychosocial stress.1–3 Activation of these systems culminates in increased inflammation and leukopoiesis that have a systemic impact through cellular migration and cytokine release.1,2 This enhanced systemic inflammatory state is closely coupled with neuroinflammation. Neuroinflammation is caused by the activation of microglia and may result from either local injury or an insult to another organ, such as the heart, through its intimate link to the peripheral immune system.1 Over time, neuroinflammation results in neurodegeneration, whereas peripheral inflammation contributes to the progression of CVD risk factors, such as diabetes, hypertension, and hyperlipidemia, as well as CVDs, such as atherosclerosis and heart failure.1,2 This feedforward loop between the heart and brain manifests as a potentially bidirectional and cyclical neuroimmune process that propagates itself once an initial injury occurs to either organ and contributes to disease in both.1

Fig. 1.

Fig. 1.

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Mechanistic outline of the potentially bidirectional cross talk between the heart and brain.

Psychosocial stress activates stress-responsive neural networks (that include fear-responsive brain regions, such as the amygdala, as well as regulatory cortical regions) and modulates the autonomic nervous system and HPA axis to culminate in changes in blood pressure and heart rate as well as heightened inflammation.2 In addition, there are important sex variations in the stress response. Women with CAD are more likely to have mental stress-induced (but not exercise-induced) ischemia than their male counterparts.18,19 As a consequence of stress hormones, men have higher baseline sympathetic tone, whereas women have greater baseline parasympathetic tone.20 Despite these differences, women appear to be more susceptible to the adverse consequences of sympathetic hyperactivity.21 Furthermore, there are important sex differences in inflammation, as women have a greater inflammatory response to stress and higher baseline C-reactive protein levels.22,23 Accordingly, stress may act variably through these neuroimmune mechanisms to result in the development of CVD risk factors, atherosclerosis, Takotsubo syndrome, sudden cardiac death, and cognitive impairment in both sexes and provide another avenue to activate this complex heart-brain relationship.2,14,24,25

The importance of these relationships in linking the heart and brain was strengthened by a recent study that provided novel insights into the neuroimmune cardiovascular interfaces contributing to atherosclerosis in both mice and humans. The findings provide further supportive evidence of a biological link involving the central nervous system, including the amygdala, and the peripheral nervous system that drives atherosclerosis and can be attenuated by ligation of the splenic nerve, resulting in decreased autonomic input, inflammation, and atherosclerotic disease.24,26

Radiotracers

Radiotracers targeting heart-brain connections continue to emerge (Table 1). Many of these radiotracers can provide an evaluation of both organs; however, the blood-brain barrier precludes the implementation of several for brain imaging. Nevertheless, some of the radiotracers that cannot penetrate the central nervous system still provide mechanistic insights through the evaluation of their peripheral uptake.

Table 1.

Radiotracers targeting pathways contributing to the heart-brain connection

System Target Example Radiotracers Cross Healthy Blood-Brain Barrier?
Inflammation and metabolism Glucose utilization 18F-FDG Yes
Chemokines/cytokines 68Ga-DOTA-ECL1 (CCR2), 68Ga-pentixafor (CXCR4) No
Immune cell metabolism 11C-methionine Yes
18-kDa translocator protein (TSPO) 11C-PBR28, 11C-PK11195, 18F-DPA714, 18F-GE180 Yes
Activated macrophages 68Ga-DOTATATE No
Autonomic regulation Sympathetic nervous system 11C-HED, 18F-FDOPA, 123I-MIBG 18F-FDOPA
Parasympathetic nervous system 11C-MQNB, 18F-F-DEX, 18F-FEOBV 18F-F-DEX, 18F-FEOBV
Renin-angiotensin system 11C-KR31173 No
Vasculature and perfusion Perfusion 15O-water, 13N-ammonia, 82Rb, 99mTc-sestamibi 15O-water, 13N-ammonia
Microcalcification 18F-sodium fluoride No
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18F-fluorodeoxyglucose (FDG) -PET has been extensively leveraged by systems-based approaches. 18F-FDG provides an assessment of glucose metabolism throughout the body and is taken up with high avidity in tissues with high metabolic rates, such as the brain, myocardium, inflammatory cells, and malignant tumors. Furthermore, uptake of 18F-FDG within the arterial wall is a validated measure that correlates with the degree of inflammatory cell infiltration and associates with downstream CVD risk.2 In several recent studies, the relationships between arterial 18F-FDG uptake and that of other organs have been explored. These studies have shown that increased resting metabolic activity in stress-associated neural networks (ie, the ratio of amygdalar to regulatory cortical uptake) and in leukopoietic tissues (ie, the bone marrow and spleen) associates with heightened inflammation in the arterial wall in individuals without CVD as well as those with acute MI.24,27 Furthermore, this neural network activity associates with perceived stress scores as well as common psychosocial stressors, such as neighborhood income and transportation noise exposure.24,28,29 Moreover, these neural changes may have a greater impact on inflammation and CVD in women.22,30 Interestingly, increased uptake in the same neural networks has also been associated with the onset and timing of Takotsubo syndrome.14 On the other hand, a recent study showed that heightened cardiovascular risk scores and carotid plaque burden associate with lower global cerebral metabolic activity on 18F-FDG-PET, providing further evidence of systemic crosstalk and complex interplay between the brain and heart.31 Although 18F-FDG provides useful insights into inflammatory atherosclerosis, other radiotracers, such as 18F-sodium fluoride and 68Ga-tetraazacyclododecane tetraacetic acid octreotate (DOTATATE), that detect microcalcifications and somatostatin receptors, respectively, provide additional information about plaque biology and CVD risk.32,33

Perfusion tracers have provided additional insights into the heart-brain connection by clarifying how each organ responds to stimuli and therapies. Perfusion of both organs can be measured with PET imaging; however, the short half-lives of the commonly implemented radiotracers often require multiple imaging positions (and therefore multiple injections) to accurately evaluate first-pass imaging. Even still, increased perfusion measured in stress-responsive brain regions under conditions of mental stress using 15O-water PET has been associated with shortened telomeres, a marker of aging, in white blood cells in patients with known CAD.34 Furthermore, mental stress has long been known to provoke ischemia on SPECT myocardial perfusion imaging.35 Further evaluation with SPECT myocardial perfusion imaging has compared the prognostic impact of mental stress-induced and conventional stress-induced ischemia.36,37 Interestingly, those with conventional stress-induced myocardial ischemia are more likely to have obstructive epicardial CAD, whereas those with mental stress-induced ischemia without ischemia induced by conventional stress are more likely to have endothelial and microvascular dysfunction.35 Moreover, those with both mental stress and conventional stress-induced ischemia had the greatest risk for CVD death or nonfatal MI followed by those with mental stress-induced ischemia alone.37 Similarly, among patients with CAD, mental stress-induced ischemia on PET myocardial perfusion imaging using 13N-ammonia associates with a worse prognosis than ischemia induced by conventional methods.37 These findings suggest that the pathologic links involve both epicardial atherosclerotic lesions and coronary microvascular dysfunction.

Several other radionuclides have become available to facilitate imaging of neurohormonal pathways that participate in the heart-brain connection. The renin-aldosterone system contributes to the response to tissue injury and can be imaged in both the heart and the brain via 11C-KR31173, a PET radiotracer that binds to the angiotensin II type I receptor.38

The autonomic nervous system can also be interrogated by several tracers that are specific to either the sympathetic or the parasympathetic nervous system. These systems directly connect the brain and heart and act through leukopoietic tissues to contribute to changes in hemodynamics, cardiac rhythm, myocardial contractility, and systemic inflammation.1,39 Sympathetic activity is chronically upregulated in heart failure as well as in cerebral and myocardial ischemia, and it contributes to increased inflammation, leukopoiesis, and HPA axis activity.1,2,39 Radiotracers that allow the assessment of myocardial sympathetic innervation include 123I-meta-iodobenzylguanidine (MIBG) for SPECT imaging and 11C-hydroxyephedrine (HED) and 18F-fluorodopa (FDOPA) for PET imaging.40–42 Notably, FDOPA has also been applied to assess autonomic dysfunction in primary neurologic diseases (eg, Parkinson disease).41 Alternatively, several other radiotracers target the parasympathetic nervous system, which counteracts the sympathetic nervous system, through their affinity to targets in cholinergic neurons. Examples include 11C-methylquinuclidinyl benzilate (MQNB), 18F-fluorobenzyl dexetimide (F-DEX), and 18F-fluoroethoxy-benzovesamicol (FEOBV).43–45

Beyond 18F-FDG, which is nonspecific for inflammation, many other radionuclide tracers have been developed to target this critical process and have provided important insights into the role of inflammation in the heart-brain connection. These tracers exhibit different patterns of uptake in different leukocyte populations, allowing them to differentially characterize the actions of the immune system in different tissues.46

Tracers targeting the 18-kDa translocator protein (TSPO) have been particularly informative. These tracers bind to a protein expressed by the mitochondria of activated immune cells and can cross the blood-brain barrier. Therefore, they localize to both activated peripheral macrophages and microglia to provide information about systemic and neuroinflammation. Following MI, TSPO tracers concentrate in the bone marrow and spleen for an extended period of time, indicating increased leukopoietic activity.46,47 In a murine study of MI, 18F-GE180 localized to CD68-positive macrophages in the region of MI as well as CD68-positive microglia within 1 week before declining at 4 weeks and again increasing at 8 weeks.48 Interestingly, the delayed increase in neural 18F-GE180 uptake at 8 weeks, which predominately occurred in the frontal cortex, was inversely proportional to cardiac function, which provides further argument that chronic neuroinflammation occurs consequent to chronic cardiac dysfunction. Notably, neuroinflammation did not occur in response to a skeletal muscle injury in the same study. In a human study, there were similar findings with 11C-PK11195.48 Furthermore, the observed neuroinflammation in these studies of MI was comparable to that seen after a stroke or in early Alzheimer disease, providing insights into the cause of progressive cognitive dysfunction after MI.49,50 Importantly, the uptake of both the heart and brain was decreased after MI by the administration of an angiotensin-converting enzyme inhibitor, indicating a key role for neurohormonal signaling in the development of multiorgan inflammation.47 Although these precise mechanisms require further clarification, these findings suggest that the interplay between peripheral inflammation and neuroinflammation is an important contributor to the heart-brain connection following injury to either the heart or the brain.

A recent investigation explored the impact of the SARS-CoV-2 pandemic on neuroinflammation in individuals without viral infection using a TSPO tracer. It compared healthy individuals imaged before and after the lockdown using 11C-PBR28 PET and showed heightened brain levels of TSPO activity after the lockdown compared with before. Furthermore, the individuals demonstrated nonsignificant trends toward increased interleukin-16 and monocyte chemoattractant protein-1, which both associate with greater atherosclerotic disease, after the lockdown.51 These findings suggest that neuroinflammation may also be a consequence of psychosocial stress that contributes to downstream pathologic conditions of the heart and brain.

Several other radiotracers facilitate evaluation of the role of inflammation in the heart-brain connection. 11C-methionine further characterizes the role of the immune system in the heart-brain relationship by targeting leukocyte amino acid metabolism, a process initiated at the onset of immune activation. After MI, uptake of 11C-methionine in the injured myocardium rises rapidly before subsequent proportionally increased brain uptake that localizes to astroglia.52,53 In addition, radiotracers targeting cytokines and chemokines localize to inflammatory cell infiltration. These include 68Ga-pentixafor, which targets C-X-C motif chemokine receptor 4 (CXCR4) and localizes to atherosclerotic plaques, MI, and stroke, as well as 68Ga-DOTA-ECL1, which targets C-C motif chemokine receptor 2 (CCR2) and localizes to injured myocardium.54–57 Additional radiotracers targeting neuroreceptors, such as the fast inhibitory ionotropic gamma-aminobutyric acid receptor (18F-flumazenil), have facilitated research into the emotional response to stress.58

Other Imaging Modalities

Imaging modalities aside from nuclear techniques have been leveraged to evaluate the link between the heart and brain (Fig. 2). Several insights have arisen from findings on 18F-FDG-PET imaging and concurrently acquired attenuation correction computed tomography (CT) imaging. For example, 1 such study identified a relationship between an increased ratio of 18F-FDG uptake in the amygdala relative to cortical tissue and increased visceral adiposity, an important CVD risk factor.59 In a study of patients with psoriasis, heightened 18F-FDG uptake in the amygdala relative to cortical tissue associated with greater coronary plaque burden on CT-angiography.60 Other studies have implemented structural and functional MRI to evaluate the heart-brain connection. Studies of patients with prior Takotsubo syndrome demonstrated altered regional brain volumes and connectivity relative to controls.61–63 Accordingly, several other imaging tools offer complementary insights that further the understanding of this relationship beyond those derived from molecular imaging.

Fig. 2.

Fig. 2.

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Application of various imaging modalities to visualize mechanisms underlying the heart-brain relationship. (A) Visualizing autonomic regulation using functional MRI (A1), 123I-mIBG-SPECT (A2), and 11C-mHED-PET (A3). (B) 18F-FDG-PET images of metabolism and inflammation with increased 18F-FDG uptake in the right amygdala (B1; white arrow), myocardium (B2), and bone marrow (B3). (C) CCTA imaging of calcified and noncalcified atherosclerotic plaques shows mid-RCA-positive remodeling (C1), mid-LAD calcified plaque (C2), and mid-LCx spotty calcification (C3). Red boxes show the cross-sectional view at the level of the corresponding plaque for each vessel. (D) Myocardial perfusion images show a reversible myocardial perfusion defect of the inferior wall of the left ventricle during stress (D1) versus rest (D2). Low MBF (mL/g/min) in the myocardial territory supplied by the LAD (D3) did not increase during stress (D3) as compared with rest (D4). 11C-mHED, 11C-meta-hydroxyephedrine; 123I-mIBG, 123I-metaiodobenzylguanidine; 13N-NH3, 13N-ammonia; 99Tc-MIBI, 99Technetium-methoxyisobutyl isonitrile; CCTA, coronary computed tomography angiography; fMRI, functional magnetic resonance imaging; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; MBF, myocardial blood flow; MR, magnetic resonance; RCA, right coronary artery; SUV, standard uptake value. (From Rossi A, Mikail N, Bengs S, et al. Heart-brain interactions in cardiac and brain diseases: why sex matters. Eur Heart J. 2022;43(39):3971-3980.)

SUMMARY

Greater recognition of the neuroimmune axis and its component mechanisms that underlie the heart-brain connection will result in greater clinical recognition and attention to factors that contribute to heightened crosstalk between these organs. Molecular imaging is uniquely positioned to study the heart-brain connection through its capacity to perform targeted whole-body imaging with a variety of tracers that characterize biological processes, such as perfusion, metabolism, autonomic nervous system and neurohormonal activity, and inflammation. Although additional research is needed (Box 1), these tracers can be leveraged in conjunction with other imaging modalities and serologic biomarkers to further refine the understanding of the underlying biology and how it varies between sexes. Furthermore, these same techniques can then be used to identify potential therapies as well as evaluate their impact on disparate tissues and biological intermediaries with the goal of reducing the consequent disease in both the heart and the brain.

Box 1. Key future directions of radionuclide imaging of the heart-brain connection.

  1. Establishing and validating the efficacy of currently available radiotracers to expand clinical recognition and access

  2. Developing, validating, and implementing new radiotracers that allow further characterization of complex multisystem biology

  3. Leveraging imaging findings to assess the effectiveness of targeted interventions

  4. Evaluating the association between radionuclide imaging findings and findings on different imaging modalities

  5. Integrating imaging-derived data with genetics, clinical phenotypes, and systemic biomarkers to make novel discoveries

CLINICS CARE POINTS.

  • Increasing evidence supports the presence of an important link between the heart and brain that contributes to pathologic condition in both organs.

  • Nevertheless, this relationship is often overlooked clinically because the biological pathways linking the 2 organs are complex and have been challenging to disentangle.

  • Molecular nuclear imaging provides a significant opportunity to evaluate a variety of contributory mechanisms simultaneously in disparate tissues, including inflammation, autonomic nervous and neurohormonal system activity, metabolism, and perfusion.

  • Although many of these molecular imaging approaches are not yet available clinically, the insights generated from ongoing research will increase clinical awareness of the heart-brain connection and may yield novel insights into potential therapeutic approaches.

KEY POINTS.

  • Growing evidence supports a complex pathologic interplay between the heart and brain that has been challenging to clarify and has important differences between sexes.

  • Molecular imaging is uniquely equipped to provide novel insights into the heart-brain connection through its ability to simultaneously evaluate biological processes in disparate tissues.

  • Radiotracers targeting processes, such as inflammation, autonomic nervous and neurohormonal system activity, metabolism, and perfusion, have elucidated important aspects of the relationship between the heart and brain.

  • An enhanced understanding of the underlying mechanisms may lead to greater clinical attention and improved patient care.

DISCLOSURE

Dr M.T. Osborne is supported in part by the United States National Institutes of Health K23HL151909 and receives consulting fees from WCG Intrinsic Imaging, LLC for unrelated work. Dr A. Tawakol is supported in part by the United States National Institutes of Health (NIH R01AR077187, R01HL152957, R01HL137913, P01HL131478, R01HL149516), International Atomic Energy Agency, and Lung Biotechnology, Inc for unrelated work. Drs S. Abohashem and S.S. Grewal have no disclosures.

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