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Purpose: Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI., Methods: C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology., Results: Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation., Conclusions: Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1β), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-β binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS), an acute cardiac condition characterized by transient wall motion abnormalities mostly of the left ventricle, results in difficulties in diagnosing patients. We set out to present a detailed blood analysis of TTS patients analyzing novel markers to understand the development of TTS. Significant differences in proinflammatory cytokine expression patterns and sex steroid and glucocorticoid receptor (GR) expression levels were observed in the TTS patient collected. Remarkably, the measured catecholamine serum concentrations determined from TTS patient blood could be shown to be two orders of magnitude lower than the levels determined from experimentally induced TTS in laboratory animals. Consequently, the exposure of endothelial cells and cardiomyocytes in vitro to such catecholamine concentrations did not damage the cellular integrity or function of either endothelial cells forming the blood–brain barrier, endothelial cells derived from myocardium, or cardiomyocytes in vitro. Computational analysis was able to link the identified blood markers, specifically, the proinflammatory cytokines and glucocorticoid receptor GR to microRNA (miR) relevant in the ontogeny of TTS (miR-15) and inflammation (miR-21, miR-146a), respectively. Amongst the well-described risk factors of TTS (older age, female sex), inflammaging-related pathways were identified to add to these relevant risk factors or prediagnostic markers of TTS. [ABSTRACT FROM AUTHOR]

An increasing number of patients are living with chronic ischemic cardiomyopathy (ICM) and/or heart failure. Treatment options and prognostic tools are lacking for many of these patients. Our aim was to investigate the prognostic value of imaging angiogenesis and macrophage activation via positron emission tomography (PET) in terms of functional improvement after cell therapy. Myocardial infarction was induced in rats. Animals were scanned with [18F]FDG PET and echocardiography after four weeks and randomized to allogeneic adipose tissue-derived stromal cells (ASCs, n = 18) or saline (n = 9). Angiogenesis and macrophage activation were assessed before and after treatment by [68Ga]Ga-RGD and [64Cu]Cu-DOTATATE. There was no overall effect of the treatment. Rats that improved left ventricular ejection fraction (LVEF) had higher uptake of both [68Ga]Ga-RGD and [64Cu]Cu-DOTATATE at follow-up (p = 0.006 and p = 0.008, respectively). The uptake of the two tracers correlated with each other (r = 0.683, p = 0.003 pre-treatment and r = 0.666, p = 0.004 post-treatment). SUVmax at follow-up could predict improvement in LVEF (p = 0.016 for [68Ga]Ga-RGD and p = 0.045 for [64Cu]Cu-DOTATATE). High uptake of [68Ga]Ga-RGD and [64Cu]Cu-DOTATATE PET after injection of ASCs or saline preceded improvement in LVEF. The use of these tracers could improve the monitoring of heart failure patients in treatment. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this paper is to provide a focused update on recent advances in non-18F-FDG radiotracers for myocardial inflammatory diseases, with a focus on cardiac sarcoidosis and myocarditis. Recent Findings: Novel radiotracers targeting molecular features of inflammation have the potential to visualize underlying molecular mechanisms key to the pathogenesis of inflammatory cardiomyopathies such as sarcoidosis and myocarditis. These radiotracers may provide unique opportunities for improved mechanistic insight, higher specificity, and better quantification of disease activity, as well as potential for guidance and monitoring of immunomodulatory therapies. Summary: Novel radiotracers provide unique possibilities in diagnosis, prognostic performance, and therapy guidance for cardiac sarcoidosis and myocarditis. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and systolic dysfunction. In most cases, DCM is progressive, leading to heart failure (HF) and death. This cardiomyopathy has been considered a common and final phenotype of several entities. DCM occurs when cellular pathways fail to maintain the pumping function. The etiology of this disease encompasses several factors, such as ischemia, infection, autoimmunity, drugs or genetic susceptibility. Although the prognosis has improved in the last few years due to red flag clinical follow-up, early familial diagnosis and ongoing optimization of treatment, due to its heterogeneity, there are no targeted therapies available for DCM based on each etiology. Therefore, a better understanding of the mechanisms underlying the pathophysiology of DCM will provide novel therapeutic strategies against this cardiac disease and their different triggers. MicroRNAs (miRNAs) are a group of small noncoding RNAs that play key roles in post-transcriptional gene silencing by targeting mRNAs for translational repression or, to a lesser extent, degradation. A growing number of studies have demonstrated critical functions of miRNAs in cardiovascular diseases (CVDs), including DCM, by regulating mechanisms that contribute to the progression of the disease. Herein, we summarize the role of miRNAs in inflammation, endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, autophagy, cardiomyocyte apoptosis and fibrosis, exclusively in the context of DCM. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS) is a severe but reversible acute heart failure syndrome that occurs following high catecholaminergic stress. TTS patients are similar to those with acute coronary syndrome, with chest pain, dyspnoea and ST segment changes on electrocardiogram, but are characterised by apical akinesia of the left ventricle, with basal hyperkinesia in the absence of culprit coronary artery stenosis. The pathophysiology of TTS is not completely understood and there is a paucity of evidence to guide treatment. The mechanisms of TTS are thought to involve catecholaminergic myocardial stunning, microvascular dysfunction, increased inflammation and changes in cardiomyocyte metabolism. Here, we summarise the available literature to focus on the molecular basis for the pathophysiology of TTS to advance the understanding of the condition. [ABSTRACT FROM AUTHOR]

Aims Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. Methods and results An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P  = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P  < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P  > 0.0001). Both lactate and pyruvate were lower (P  < 0.05) despite increases in LDH-RNA and PDH (P  < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P  < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P  = 0.01) with decreased fatty acids and acyl-carnitines levels (P  = 0.0001–0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P  < 0.05) as was cellular ATP reporter dihydroorotate (P  = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P  < 0.0001), inducing the oxidation of NAD(P)H and FAD (P  = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated—increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P  < 0.05). Conclusion Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity. [ABSTRACT FROM AUTHOR]

This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including β‐adrenergic receptor signalling, G‐protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model. [ABSTRACT FROM AUTHOR]

Persistent inflammation following myocardial infarction (MI) precipitates adverse outcome including acute ventricular rupture and chronic heart failure. Molecular imaging allows longitudinal assessment of immune cell activity in the infarct territory and predicts severity of remodeling. We utilized a multiparametric imaging platform to assess the immune response and cardiac healing following MI in mice. Suppression of circulating macrophages prior to MI paradoxically resulted in higher total leukocyte content in the heart, demonstrated by increased CXC motif chemokine receptor 4 (CXCR4) positron emission tomography imaging. This supported the formation of a thrombus overlying the injured region, as identified by magnetic resonance imaging. The injured and thrombotic region in macrophage depeleted mice subsequently showed active calcification, as evidenced by accumulation of 18F-fluoride and by cardiac computed tomography. Importantly, macrophage suppression triggered a prolonged inflammatory response confirmed by post-mortem tissue analysis that was associated with higher mortality from ventricular rupture early after occlusion and with increased infarct size and worse chronic contractile function at 6 weeks after reperfusion. These findings establish a molecular imaging toolbox for monitoring the interplay between adverse immune response and tissue repair after MI. This may serve as a foundation for development and monitoring of novel targeted therapies that may include immune modulation and endogenous healing support. [ABSTRACT FROM AUTHOR]

Purpose of Review: To examine the use of positron emission tomography (PET) for imaging post-infarct myocardial inflammation and repair. Recent Findings: Dysregulated immune responses after myocardial infarction are associated with adverse cardiac remodelling and an increased likelihood of ischaemic heart failure. PET imaging utilising novel tracers can be applied to visualise different components of the post-infarction inflammatory and repair processes. This approach could offer unique pathophysiological insights that could prove useful for the identification and risk-stratification of individuals who would ultimately benefit most from emerging immune-modulating therapies. PET imaging could also bridge the clinical translational gap as a surrogate measure of drug efficacy in early-stage clinical trials in patients with myocardial infarction. The use of hybrid PET/MR imaging, in particular, offers the additional advantage of simultaneous in vivo molecular imaging and detailed assessment of myocardial function, viability and tissue characterisation. Summary: Further research is needed to realise the true clinical translational value of PET imaging after myocardial infarction. [ABSTRACT FROM AUTHOR]

Purpose of Review: Current therapeutic strategies to mitigate heart failure progression after myocardial infarction involve support of endogenous repair through molecular targets. The capacity for repair varies greatly between individuals. In this review, we will assess how cardiac PET/CT enables precise characterization of early pathogenetic processes which govern ventricle remodeling and progression to heart failure. Recent Findings: Inflammation in the first days after myocardial infarction predicts subsequent functional decline and can influence therapy decisions. The expansion of anti-inflammatory approaches to improve outcomes after myocardial infarction may benefit from noninvasive characterization using imaging. Novel probes also allow visualization of fibroblast transdifferentiation and activation, as a precursor to ventricle remodeling. Summary: The expanding arsenal of molecular imaging agents in parallel with new treatment options provides opportunity to harmonize diagnostic imaging with precision therapy. [ABSTRACT FROM AUTHOR]

Purpose: Many radioligands have been developed for the visualization of atherosclerosis by targeting inflammation. However, interpretation of in vivo signals is often limited to plaque identification. We evaluated binding of some promising radioligands in an in vitro approach in atherosclerotic plaques with different phenotypes. Methods: Tissue sections of carotid endarterectomy tissue were characterized as early plaque, fibro-calcific plaque, or phenotypically vulnerable plaque. In vitro binding assays for the radioligands [111In]In-DOTATATE; [111In]In-DOTA-JR11; [67Ga]Ga-Pentixafor; [111In]In-DANBIRT; and [111In]In-EC0800 were conducted, the expression of the radioligand targets was assessed via immunohistochemistry. Radioligand binding and expression of radioligand targets was investigated and compared. Results: In sections characterized as vulnerable plaque, binding was highest for [111In]In-EC0800; followed by [111In]In-DANBIRT; [67Ga]Ga-Pentixafor; [111In]In-DOTA-JR11; and [111In]In-DOTATATE (0.064 ± 0.036; 0.052 ± 0.029; 0.011 ± 0.003; 0.0066 ± 0.0021; 0.00064 ± 0.00014 %Added activity/mm2, respectively). Binding of [111In]In-DANBIRT and [111In]In-EC0800 was highest across plaque phenotypes, binding of [111In]In-DOTA-JR11 and [67Ga]Ga-Pentixafor differed most between plaque phenotypes. Binding of [111In]In-DOTATATE was the lowest across plaque phenotypes. The areas positive for cells expressing the radioligand's target differed between plaque phenotypes for all targets, with lowest percentage area of expression in early plaque sections and highest in phenotypically vulnerable plaque sections. Conclusions: Radioligands targeting inflammatory cell markers showed different levels of binding in atherosclerotic plaques and among plaque phenotypes. Different radioligands might be used for plaque detection and discerning early from vulnerable plaque. [111In]In-EC0800 and [111In]In-DANBIRT appear most suitable for plaque detection, while [67Ga]Ga-Pentixafor and [111In]In-DOTA-JR11 might be best suited for differentiation between plaque phenotypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Beyond its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) is a key player in the orchestration of inflammatory responses to inflammatory stimuli. This review therefore particularly focuses on summarizing the current knowledge on non-invasive imaging of tissue infiltration with CXCR4-expressing immune cells in the context of diverse inflammatory conditions using positron emission tomography. An overview of the current clinical and preclinical approaches in this context is provided, and the recent advances in the development of dedicated, high-end CXCR4-targeted imaging tools and theranostic agents are discussed. Given its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) has attracted a lot of interest in the field of nuclear oncology, and clinical evidence on the high potential of CXCR4-targeted theranostics is constantly accumulating. Additionally, since CXCR4 also represents a key player in the orchestration of inflammatory responses to inflammatory stimuli, based on its expression on a variety of pro- and anti-inflammatory immune cells (e.g., macrophages and T-cells), CXCR4-targeted inflammation imaging has recently gained considerable attention. Therefore, after briefly summarizing the current clinical status quo of CXCR4-targeted theranostics in cancer, this review primarily focuses on imaging of a broad spectrum of inflammatory diseases via the quantification of tissue infiltration with CXCR4-expressing immune cells. An up-to-date overview of the ongoing preclinical and clinical efforts to visualize inflammation and its resolution over time is provided, and the predictive value of the CXCR4-associated imaging signal for disease outcome is discussed. Since the sensitivity and specificity of CXCR4-targeted immune cell imaging greatly relies on the availability of suitable, tailored imaging probes, recent developments in the field of CXCR4-targeted imaging agents for various applications are also addressed. [ABSTRACT FROM AUTHOR]

First recognized in 1990, takotsubo syndrome (TTS) constitutes an acute cardiac condition that mimics acute myocardial infarction commonly in the absence of obstructive coronary artery disease; it is characterized by temporary left ventricular dysfunction, regularly in a circumferential apical, midventricular, or basal distribution. Considering its acute clinical presentation, coronary angiography with left ventriculography constitutes the gold standard diagnostic tool to exclude or confirm TTS. Frequently, TTS is related to severe emotional or physical stress and a subsequent increased adrenergic stimulation affecting cardiac function. Beyond clinical presentation, epidemiology, and novel diagnostic biomarkers, this review draws attention to potential pathophysiological mechanisms for the observed reversible myocardial dysfunction such as sympathetic overdrive-mediated multi-vessel epicardial spasms, microvascular dysfunction, the direct toxicity of catecholamines, lipotoxicity, and inflammation. Considering the long-term prognosis, further experimental and clinical research is indispensable to elucidate further pathophysiological mechanisms underlying TTS before randomized control trials with evidence-based therapeutic management can be performed. [ABSTRACT FROM AUTHOR]

The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings. [ABSTRACT FROM AUTHOR]

Purpose of Review: To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field. Recent Findings: While PET imaging with 18F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Summary: Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases. [ABSTRACT FROM AUTHOR]