Author + information
- Received October 13, 2017
- Revision received November 1, 2017
- Accepted November 6, 2017
- Published online January 15, 2018.
- James T. Thackeray, PhDa,
- Henri C. Hupea,
- Yong Wang, MDb,
- Jens P. Bankstahl, PhDa,
- Georg Berding, MDa,
- Tobias L. Ross, PhDa,
- Johann Bauersachs, MDb,
- Kai C. Wollert, MDb and
- Frank M. Bengel, MDa,∗ ()
- aDepartment of Nuclear Medicine, Hannover Medical School, Hannover, Germany
- bDepartment of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
- ↵∗Address for correspondence:
Dr. Frank M. Bengel, Department of Nuclear Medicine, Hannover Medical School, Carl Neuberg-Strasse 1, D-30625 Hannover, Germany.
Background The local inflammatory tissue response after acute myocardial infarction (MI) determines subsequent healing. Systemic interaction may induce neuroinflammation as a precursor to neurodegeneration.
Objectives This study sought to assess the influence of MI on cardiac and brain inflammation using noninvasive positron emission tomography (PET) of the heart-brain axis.
Methods After coronary artery ligation or sham surgery, mice (n = 49) underwent serial whole-body PET imaging of the mitochondrial translocator protein (TSPO) as a marker of activated macrophages and microglia. Patients after acute MI (n = 3) were also compared to healthy controls (n = 9).
Results Infarct mice exhibited elevated myocardial TSPO signal at 1 week versus sham (percent injected dose per gram: 8.0 ± 1.6 vs. 4.8 ± 0.9; p < 0.001), localized to activated CD68+ inflammatory cells in the infarct. Early TSPO signal predicted subsequent left ventricular remodeling at 8 weeks (rpartial = −0.687; p = 0.001). In parallel, brain TSPO signal was elevated at 1 week (1.7 ± 0.2 vs. 1.4 ± 0.2 for sham; p = 0.017), localized to activated microglia. After interval decline at 4 weeks, progressive heart failure precipitated a second wave of neuroinflammation (1.8 ± 0.2; p = 0.005). TSPO was concurrently up-regulated in remote cardiomyocytes at 8 weeks (8.8 ± 1.7, p < 0.001) without inflammatory cell infiltration, suggesting mitochondrial impairment. Angiotensin-converting enzyme inhibitor treatment lowered acute inflammation in the heart (p = 0.003) and brain (p = 0.06) and improved late cardiac function (p = 0.05). Patients also demonstrated elevation of cardiac TSPO signal in the infarct territory, paralleled by neuroinflammation versus controls.
Conclusions The brain is susceptible to acute MI and chronic heart failure. Immune activation may interconnect heart and brain dysfunction, a finding that provides a foundation for strategies to improve heart and brain outcomes.
- heart failure
- myocardial infarction
- positron emission tomography
The complex, multifaceted interaction between the cardiovascular and central nervous systems is increasingly emphasized as a contributor to degenerative disease. Impairment of one organ may contribute to dysfunction of another. Common mechanisms may provide not only novel pathogenetic insights but may also facilitate the development of reparative therapies (1,2).
Cognitive impairment is more frequent among individuals with previous myocardial infarction (MI) or congestive heart failure than in the healthy population (3–5). Likewise, unrecognized MI is associated with increased risk of Alzheimer’s dementia (6), and the extent of coronary artery disease has been linked with Alzheimer’s disease–associated neuropathology (7). Microvascular dysfunction, neurohormonal activation, and oxidative stress may be contributors, but the precise underlying mechanisms have not yet been elucidated (2).
Inflammation may be a potential linker of brain and heart dysfunction. Acute MI triggers a local and systemic inflammatory response, which accelerates atherosclerosis, activates the autonomic nervous system, and contributes to left ventricular remodeling (8,9). Chronic heart failure is associated with elevated systemic levels of proinflammatory cytokines, which are further associated with progression and adverse outcome (10,11). In contrast, the brain is rich in microglia, which is the main agonist in neuroinflammation—the central nervous immune response to local damage or systemic activation (12). Neuroinflammation is thought to be a key for the progression of Alzheimer’s dementia (13), in which microglia are activated by amyloid deposits and exert neurotoxic effects, which further aggravate inflammation and amplify amyloid deposition (14).
We hypothesized that the immune response to local myocardial damage is systemically associated with neuroinflammation. If successfully established, such a link may serve to explain accelerated cognitive dysfunction in heart disease and may provide a basis for development of novel therapies. To test our hypothesis, we used serial noninvasive whole-body positron emission tomography (PET) for simultaneous interrogation of the heart and brain. Our specific PET imaging agents targeted the 18-kDa mitochondrial translocator protein (TSPO), which is up-regulated in activated microglia and in systemic monocytes (14). Results in experimental models were validated by ex vivo tissue analysis, and their translational relevance was shown in a clinical imaging project.
C57Bl/6 mice underwent coronary artery ligation (n = 43) or sham surgery (n = 9). A subgroup of infarct mice (n = 10) received continuous treatment with the angiotensin-converting enzyme Enalapril (20 mg/kg/day), administrated orally beginning 3 days before surgery until 8 weeks post-MI. The selected dose has been demonstrated to reduce activated inflammatory leukocyte homing to the infarct territory in the acute stages after MI without effect on blood pressure (4,5).
MI was induced by ligation of the left coronary artery as previously described (5). Briefly, mice were pre-treated with the analgesic butorphanol (2 mg/kg subcutaneously) and anesthetized by isoflurane (induction at 3% to 4%, maintained at 1.5% to 2% after oral intubation under mechanical ventilation). A left thoracotomy and opening of the pericardium were performed, and a ligature was placed around the left anterior descending coronary artery. For sham operations, the ligature was not secured. In an additional subgroup of animals, the left coronary artery was occluded for 60 min, followed by reperfusion (n = 6) to more accurately model the clinical setting with revascularization.
Lipopolysaccharide-induced hindlimb inflammation
To validate the cardiac specificity of the inflammatory response, localized inflammation was induced by intramuscular injection of 27 μg of lipopolysaccharide (n = 6) in a 30-μl bolus to the left gastrocnemius. This inoculation leads to immune activation and increased migration of leukocytes to the inflamed region and has been suggested to increase cytokine levels and affect blood-brain barrier permeability (6–8). Control animals (n = 3) received saline alone. Inflammation is stable in the affected region more than 1 week after inoculation.
Whole-body small-animal PET
Scans with 18F-GE180 were performed 3 days, 7 days, 4 weeks, and 8 weeks post-MI using an Inveon DPET (Siemens, Knoxville, Tennessee) according to imaging procedures previously described (3,9). Briefly, mice were anesthetized with isoflurane (inhalation, 1.5% at 0.6 l/min), and 18F-GE180 (14.2 ± 2.8 MBq) was injected as a 0.10- to 0.15-ml bolus via lateral tail vein catheter, directly followed by a 0.1-ml flush of heparinized saline. From beginning of tracer injection, a 60-min dynamic acquisition scan was started with heart rate and respiration continuously measured. A 57Co point source–based transmission scan was used for attenuation correction. At the conclusion of the PET image acquisition, low-dose computed tomography was conducted for coregistration of the PET signal.
To define specific binding, a subgroup of healthy control (n = 4) and MI mice (n = 4) received coadministration of the unlabeled TSPO inhibitor PK11195 (1 mg/kg intravenously). Whenever possible, mice were scanned serially at each time point (n = 24). Animals that did not survive the complete 8 weeks of the study were excluded from final analysis. Because there was no statistical difference in tracer uptake at 3 days and 7 days post-MI, we focused on tracer uptake data at day 7 as representative of the first week after MI in subsequent analyses. Full detailed methods are available in the Online Appendix.
TSPO-targeted PET imaging agent 18F-GE180 binds specifically to mitochondria-rich organs and inflammatory cells
Whole-body biodistribution of 18F-GE180 in healthy mice showed predominant accumulation in lymphoid organs such as the spleen and bone marrow, but also in myocardium as a tissue rich in active mitochondria. TSPO specificity was confirmed by blockade after pretreatment with the unlabeled ligand PK11195 (Online Figures 1A and 1B). Nonspecific binding in the kidney and liver was higher than in other organs, reflecting tracer clearance through the biliary and renal systems. Baseline uptake in the normal brain was low, while specificity for activated microglia has been confirmed previously in models of neuroinflammation (15,16).
In vitro, proinflammatory M1-polarized macrophages exhibited 7-fold higher uptake compared to reparative M2 macrophages (10.7 ± 2.1% vs. 1.6 ± 0.6%; p < 0.001) (Online Figure 2A). Among peripheral leukocytes, uptake was highest in CD11b+ cells of monocyte/macrophage lineage (3.2 ± 1.3%), with modestly lower uptake in CD177+ neutrophils (1.7 ± 0.3%; p = 0.027) and significantly lower uptake in lymphocytes (1.1 ± 0.3%; p = 0.022) (Online Figure 2B).
Regionally elevated cardiac TSPO signal early after MI identifies post-infarct tissue inflammation
In mice, permanent ligation of the left anterior descending coronary artery generated MI, characterized by a perfusion defect affecting 47 ± 10% of the left ventricle. In the first week after MI, global cardiac 18F-GE180 uptake was elevated by 65% compared to sham operation (Figures 1A and 1B). Uptake at 3 days and 7 days post-MI was comparable (Online Figures 3 and 3B). Polar map analysis localized elevated uptake relative to regional perfusion predominantly to the infarct region (Figures 1A and 1C), and remote myocardial activity was mildly elevated (Figures 1D and 1E). Ex vivo autoradiography confirmed in vivo images (Online Figures 3C and 3D). Immunostaining and dual fluorescence microscopy colocalized the elevated TSPO signal in the infarct to abundant CD68+ inflammatory cells (Figures 1F and 1G).
Elevated cardiac TSPO signal late after MI is associated with left ventricular remodeling
By 4 weeks post-MI, the myocardial TSPO signal declined to levels that were not different from sham operation. At 8 weeks, however, the signal was elevated again by 80% over sham (Figures 1A and 1B). Regional analysis showed that, unlike in week 1, this was due to significantly elevated remote myocardial activity (Figure 1D), but infarct signal remained low (Figure 1C). Ex vivo tissue analysis confirmed TSPO elevation in remote myocardium as a diffuse process involving myocardial tissue, but CD68+ inflammatory cells were mostly absent (Figures 1F and 1G). Serial analysis of left ventricular function and geometry after MI describes continuously declining ejection fraction, along with increasing volumes and heart and lung weight (Figures 2A to 2F) over 8 weeks. This finding confirms left ventricular remodeling leading to heart failure. Reappearance of elevated TSPO signal in the absence of significant inflammatory cells after 8 weeks is therefore associated with progressive contractile dysfunction, which may suggest myocyte mitochondrial impairment.
TSPO signal from other organs is mostly stable after MI
To assess the presence of systemic inflammation, we evaluated peripheral organ TSPO expression in PET images. A modest increase in spleen and bone marrow TSPO was observed at 1 week post-MI, consistent with hematopoietic activation. No significant differences were observed for liver or skeletal muscle. Kidney 18F-GE180 signal was reduced at 8 weeks post-MI, which may be due to either TSPO pathology or impaired renal function in heart failure (Online Figure 4).
Early inflammation-associated cardiac TSPO signal predicts subsequent functional outcome
Global myocardial uptake of 18F-GE180 at 1 week post-MI correlated with the severity of heart failure after 8 weeks, including ventricular volumes (end-systolic volume: r = 0.673; p = 0.001; end-diastolic volume: r = 0.604; p = 0.005) and ejection fraction (r = −0.687; p < 0.001) (Figures 2G and 2H, Online Figure 5). Although infarct size at 1 week post-MI was proportional to cardiac function at 8 weeks (Online Figure 5), multivariate stepwise regression also identified global cardiac 18F-GE180 uptake at 1 week as independently associated with reduced ejection fraction at 8 weeks (rpartial = −0.62; p = 0.008).
Time course of cardiac TSPO signal is paralleled by neuroinflammation
Whole-brain 18F-GE180 uptake was elevated by 23% compared to sham (p = 0.017) at 1 week after MI, returned to normal at 4 weeks, but recurred to a similarly elevated level at 8 weeks (+24% vs. sham; p = 0.005) (Figures 3A and 3C). Parametric maps indicate that the elevated signal is located throughout the cortex (Figure 3B). Brain TSPO signal correlated with cardiac signal over the full time course of experiments (Figure 3D).
Fluorescence immunostaining of brain sections confirmed the presence of CD68+ microglia, highly expressing TSPO at 1 week, but also at 8 weeks post-MI. Astrocytes, which have been discussed as another source of TSPO signal, were identified by glial fibrillary acidic protein but did not colocalize with TSPO fluorescence (Figure 3E). TSPO and CD68 were markedly lower at 4 weeks, consistent with the imaging data.
Brain uptake of 18F-GE180 at 8 weeks was associated with ventricular dysfunction and cardiac TSPO signal at 8 weeks (Figures 3F and 3G), but also with early brain (r = 0.72; p = 0.001) and heart (r = 0.54; p = 0.025) TSPO signal at 1 week. At multivariate stepwise regression, early brain TSPO signal (rpartial = 0.73; p = 0.001), and late cardiac TSPO signal (rpartial = 0.53; p = 0.036) were independently associated with late brain TSPO signal, whereas ejection fraction, infarct size, and early cardiac TSPO signal were not (p > 0.10) (Online Figure 4).
Ischemia-reperfusion results in comparable cardiac and neuroinflammation
In a series of animals with 60 min of ischemia followed by reperfusion, uptake of 18F-GE180 was elevated in the global myocardium at 1 week post-MI, focused mainly in the region of hypoperfusion (p < 0.001). Ischemia-reperfusion–operated animals exhibited a comparable 15% increase in brain signal (p < 0.001) (Online Figure 6).
Localized skeletal muscle inflammation does not evoke cardiac or neuroinflammatory response
To assess the specificity of neuroinflammation in relation to cardiac inflammation, we induced localized inflammation by hindlimb intramuscular lipopolysaccharide injection. Injected animals showed increased bone marrow signal suggesting systemic activation and 18F-GE180 binding in the inflamed muscle. No concomitant inflammation was found in the heart or brain (Online Figure 7).
Enalapril attenuates post-infarct MI, ventricular remodeling, and neuroinflammation
To obtain further mechanistic insights, a group of mice was continuously treated with the angiotensin-converting enzyme inhibitor enalapril (20 mg/kg/day orally), beginning 2 days before surgery. This has been shown to reduce post-infarct myocardial inflammation and thereby improve functional outcome (17,18). Consistently, enalapril attenuated cardiac TSPO signal by 24% at 1 week (p = 0.003) and by 25% at 8 weeks (p = 0.011) compared to untreated MI mice (Figures 4A and 4B). Lower values at 1 week were mostly due to infarct territory reduction, whereas the difference at 8 weeks was predominantly found in remote myocardium (Online Figure 8). Enalapril also attenuated ventricular remodeling, resulting in significantly lower ventricular volumes and higher ejection fraction (Figure 4E), without affecting infarct size (Online Figure 8). Parallel to myocardial signal, neuroinflammation tended to be lower at 1 week and was significantly lower at 8 weeks compared to untreated animals (−16%; p = 0.014) (Figures 4C and 4D). No differences for the brain and heart were detected at 4 weeks.
Patients early after MI exhibit myocardial inflammation and neuroinflammation
Similar to mice, elevated myocardial TSPO signal was identified in the hypoperfused infarct region in 3 patients at 4 to 6 days after acute ST-segment elevation MI. Quantitatively, an elevation of TSPO signal relative to perfusion of 35 ± 13% was found in the infarct vessel territory (vs. 15 ± 5% for remote territories; p = 0.017) (Figure 5A). Additionally, group comparison of brain TSPO signal in infarct patients versus 9 healthy subjects without any evidence of brain or heart disease revealed elevations of up to 20%, most pronounced in temporal and frontobasal cortex, hypothalamus, and cerebellum (Figure 5B).
Using serial noninvasive whole-body molecular imaging, we simultaneously interrogated the 18-kDa translocator protein TSPO as a marker of activated immune cells in the heart and brain (Central Illustration). Our systems-based analysis included ex vivo identification of the cellular substrate of the imaging signal, confirmed the clinical translational potential of preclinical results, and provided 3 major novel insights. First, TSPO-targeted molecular imaging identifies early post-infarct myocardial inflammation, the severity of which predicts later occurrence of adverse left ventricular remodeling. Second, in addition to its value as an inflammation marker, TSPO is a mitochondrial marker that identifies myocyte dysfunction in heart failure (19). Third, and most importantly, TSPO-targeted imaging identifies cerebral microglia activation as a hallmark of neuroinflammation (15,20), which coincides with cardiac alterations both in the early phase of post-infarct myocardial inflammation and in the late phase of chronic heart failure. The observed interaction between the brain and heart is accompanied by activation of hematopoietic organs in the early but not the late phase, and it does not involve other organs in a similar way. Likewise, noncardiac skeletal muscular inflammation exerts systemic effects on hematopoietic organs but does not result in similar involvement of the brain. This finding highlights a tight interaction between heart and brain inflammation after cardiac injury, and it provides common ground for the development of preventive/regenerative therapeutic strategies aimed at improved outcome for both organs.
Neuroinflammation and cognitive impairment
The role of neuroinflammation in the development of cognitive impairment and in Alzheimer’s disease progression has been increasingly recognized. Activation of microglia is an immune response to misfolded proteins such as beta-amyloid, and it is considered necessary for clearance. But persistent or exaggerated neuroinflammation causes neurotoxicity and accelerates neurodegeneration (14). Clinical imaging studies identified neuroinflammation at sites of cortical beta-amyloid deposition and showed a relationship with cognitive decline (20,21). Larger multitracer clinical imaging trials are underway to explore the interaction in more depth (22). The present study, which is the first to look at the brain and heart simultaneously, suggests that cardiovascular disease should be considered in future cohort studies because of its neuroinflammatory effect. The biphasic neuroinflammation pattern with peaks in early acute and late chronic stages of cardiac damage shows similarity to clinical observations of a biphasic peak at initial onset of mild cognitive impairment and late advanced Alzheimer’s disease (23,24). It is also consistent with the concept of microglial priming, in which an initial primary stimulus increases subsequent microglia susceptibility (25). In our study, the systemic inflammatory response to acute MI may indeed serve as the primer for the subsequent reoccurrence in chronic heart failure. The recurrent neuroinflammation in heart failure may relate to impaired cerebral blood flow, elevated proinflammatory cytokines, and rising levels of angiotensin II (26,27). Indeed, augmented cerebral tumor necrosis factor-α was reported in mice with congestive heart failure, leading to morphological changes and cognitive impairment (26).
Cellular basis of the TSPO PET signal
Using whole-body imaging, we were able to identify the TSPO status of the heart simultaneously with that of the brain. The biphasic up-regulation occurred in both organs, but the cellular substrate differed. Fluorescence microscopy showed that the cortical TSPO signal emerges specifically from microglia at all time points. Glial fibrillary acidic protein identified astroglia, which is also involved in neuroinflammation (28), but TSPO was not expressed on those cells. In acutely infarcted myocardium, in which myocytes are nonviable because of ischemic damage, the TSPO signal is elevated as a function of infiltrating CD68+ monocytes, which are abundant within the first week after MI. Earlier studies reported no change in TSPO expression within the area at risk 24 h after ischemia and reperfusion (19). However, the present study suggests a robust increase of infarct-region TSPO within the first week, both after permanent occlusion as well as after ischemia and reperfusion. Severity of ischemia, later assessment time point, and severity of inflammation may have contributed to this difference. Of note, the severity of inflammation early after MI has been linked to adverse outcome. A recent clinical study demonstrated that the highest infarct territory accumulation of fluorodeoxyglucose within 7 days after first MI tended to result in the lowest ejection fraction at 6 months of follow-up (29). This observation is replicated in the present study in mice, in which global cardiac TSPO up-regulation at 1 week demonstrated an independent correlation with depressed ejection fraction and elevated volumes at 8 weeks.
Chronic heart failure and TSPO
Interestingly, TSPO up-regulation in the heart recurred at 8 weeks after MI, at a time when post-infarct remodeling has led to fully developed heart failure (30). Here, unlike in brain and acute infarct, TSPO signal was not associated with inflammatory cells. Rather, it localized to cardiomyocytes in remote, noninfarcted but functionally impaired myocardium. Metabolic dysfunction in the failing heart is known to be associated with mitochondrial dysfunction (31), which likely underlies this diffuse, noninflammatory up-regulation of TSPO. Consistent with this concept, global myocardial TSPO was lower at 4 weeks after MI than at either 1 or 8 weeks, suggesting a transitional phase between acute inflammation and mitochondrial dysfunction as ventricular volumes rise and ejection fraction declines. Mitochondrial abnormalities are common in terminal heart failure, including impaired electron transport chain activity, increased reactive oxygen species activation, aberrant mitochondrial dynamics, and altered ion homeostasis (31). Treatments such as elamipretide aiming to attenuate reactive oxygen species–mediated loss of energetics are gaining providence in heart failure. Thus, although the cardiac TSPO imaging signal may have a mixed cellular substrate in conditions in which inflammation and myocyte mitochondrial dysfunction may coexist, it may nevertheless be of value as a marker of outcome and for guidance and monitoring of the effects of novel inflammation- or mitochondria-targeted therapies.
Systemic inflammatory networking
The presence of systemic inflammatory networking after MI was established in previous studies demonstrating involvement of the spleen and bone marrow as reservoirs for inflammatory cells (32,33) but also in activation of atherosclerosis (8). Consistently, elevated TSPO signal in the spleen and bone marrow at 3 days after MI was consistent with systemic immune activation in our study. Other organs, such as the kidneys, which are rich in TSPO, liver, and skeletal muscle did not show the same pattern. Furthermore, induction of focal inflammation in skeletal muscle activated the hematopoietic organs but did not affect the heart and brain. These observations suggest that the brain is more tightly coupled with the heart than other nonhematopoietic organs in response to cardiac damage. The exact mechanisms for this observation are not elucidated and require further investigation. However, activation of the autonomic nervous system has long been associated with progressive heart failure and provides the basis for well-established drug therapy approaches. It also appears to be involved in liberation of cells from the bone marrow (8). Furthermore, a recent imaging study identified a relationship between activation of the amygdala (a brain region involved in stress) and arterial inflammation, bone marrow activation, and subsequent cardiovascular events, thus providing insights into the role of emotional stressors in progression of heart disease (34).
Modulating inflammation as a means of slowing the progression of cognitive decline has gained interest as a treatment strategy. TSPO inhibitors such as 4′-chlordiazepam exhibit cardioprotection in ischemia-reperfusion injury via antioxidant mechanisms, and they have also been proposed for modulating neuroinflammation (35,36). Nonsteroidal anti-inflammatory drugs demonstrated modest efficacy in preventing beta-amyloid deposition and Alzheimer’s disease progression (37,38), and experimental inhibition of peroxisome proliferator activated receptors improved cognitive performance, paralleled by a decrease in neuroinflammation (39). Treatment of Alzheimer’s disease with cholinesterase inhibitors appears to lower the incidence of MI in a dose-dependent manner (40), and our study suggests beneficial effects of enalapril, a drug established for treatment of cardiovascular conditions, on neuroinflammation. These observations underscore the interaction between heart- and brain-related disease, and they support the benefit of multiorgan molecular imaging to guide and monitor the efficacy of inflammation-targeted interventions.
First, cognitive function was not measured in our animal model, which was also not genetically predispositioned to develop brain amyloid deposits. However, the association between neuroinflammation, beta-amyloid deposition, and cognitive impairment has been extensively studied in previous experimental (39,41) and clinical studies (20), supporting the notion that post-infarct–related neuroinflammation may be detrimental to cognitive function in subjects at risk. Second, the exact mechanism of interaction between cardiac damage and neuroinflammation is not elucidated by our work. Although previous work supports a forward effect of the nervous system on cardiovascular disease, our study suggests that there are also backward effects by which cardiac damage affects the equilibrium of the brain. Recurrent neuroinflammation may result from a number of factors arising from cardiac damage, including neurohumoral activation, elevated systemic cytokines, microvascular impairment, or oxidative stress (2,11,42,43). Irrespective of the mechanism, the present results demonstrate a strong correlation between cardiac damage and the severity of neuroinflammation, which may be pursued for therapeutic intervention. Finally, the brain/heart-focused clinical imaging protocol in patients did not support in-depth analysis of other organs as in animal studies. However, the similarity of the heart and brain findings confirms the translational potential of the experimental results.
TSPO-targeted whole-body molecular imaging identifies inflammation as a crucial connection between the brain and heart after cardiac injury. Acute MI leads to an early inflammatory response, which stimulates adverse left ventricular remodeling and triggers brain microglia activation in a biphasic pattern. A systems-based, multiorgan molecular imaging strategy may assist in the development of targeted anti-inflammatory therapies that may benefit both systems by providing risk assessment, identifying therapeutic target expression, and monitoring intervention effectiveness.
COMPETENCY IN MEDICAL KNOWLEDGE: Myocardial inflammation after ischemic injury contributes to adverse remodeling, and represents a target for therapy. Neuroinflammation, detected concurrently by PET, may predict neurodegeneration and cognitive decline.
TRANSLATIONAL OUTLOOK: Future studies of the influence of therapies that modulate the inflammatory response to ischemic myocardial injury should incorporate brain imaging and serial cognitive assessments.
The authors thank the members of the preclinical molecular imaging and radiochemistry laboratories for their technical assistance with these studies.
This work was supported by the German Research Foundation (DFG: TH2161/1-1, KFO 311, and Excellence Cluster Rebirth II). Agents for synthesis of the TSPO marker 18F-GE180 were provided by GE Healthcare (Amersham, Buckinghamshire, United Kingdom), based on a materials transfer agreement. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Thackeray and Hupe contributed equally to this work and are joint first authors.
- Abbreviations and Acronyms
- myocardial infarction
- positron emission tomography
- translocator protein
- Received October 13, 2017.
- Revision received November 1, 2017.
- Accepted November 6, 2017.
- 2018 American College of Cardiology Foundation
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