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.

Targeted PET imaging with (68)Ga-pentixafor identifies the global and regional CXCR4 expression pattern in myocardium and systemic organs. CXCR4 upregulation after AMI coincides with inflammatory cell infiltration, but shows interindividual variability in patients. This may have implications for the response to CXCR4- or other inflammation-targeted therapy, and for subsequent ventricular remodeling.

AimsThe benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.Methods and resultsFollow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The β-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.ConclusionsIso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

Aims  Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. Methods and results  Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = −0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. Conclusion  Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.

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The CXC-motif chemokine receptor 4 (CXCR4) represents a promising target for molecular imaging of different CXCR4-positive cell types in cardiovascular diseases such as atherosclerosis and arterial wall injury. The aim of this study was to assess the prevalence, pattern, and clinical correlates of arterial wall accumulation of Ga-pentixafor, a specific CXCR4 ligand for PET. The data for 51 patients who underwent Ga-pentixafor PET/CT for noncardiovascular indications were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed qualitatively and semiquantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with calcified plaque burden and cardiovascular risk factors. Focal arterial uptake of Ga-pentixafor was seen at 1,411 sites in 51 (100%) of patients.Ga-pentixafor uptake was significantly associated with calcified plaque burden ( < 0.0001) and cardiovascular risk factors including age ( < 0.0001), arterial hypertension ( < 0.0001), hypercholesterolemia ( = 0.0005), history of smoking ( = 0.01), and prior cardiovascular events ( = 0.0004). Both the prevalence ( < 0.0001) and the signal intensity ( = 0.009) of Ga-pentixafor uptake increased as the number of risk factors increased.Ga-pentixafor PET/CT is suitable for noninvasive, highly specific PET imaging of CXCR4 expression in the atherosclerotic arterial wall. Arterial wall Ga-pentixafor uptake is significantly associated with surrogate markers of atherosclerosis and is linked to the presence of cardiovascular risk factors.Ga-pentixafor signal is higher in patients with a high-risk profile and may hold promise for identification of vulnerable plaque.

Continuous isoflurane anaesthesia obscures any suppressive effect of heparin or fasting on cardiomyocyte glucose utilization. Conscious injection of FDG in rodents significantly reduces cardiomyocyte uptake and enables further suppression by heparin and fasting, similar to clinical observations. In contrast to ketamine/xylazine, this represents a more physiological, translatable strategy for suppression of cardiomyocyte (18)F-FDG uptake when targeting myocardial inflammation.

We recently demonstrated in a clinical trial the ability of a new protocol, IQ SPECT, to acquire myocardial perfusion imaging (MPI) studies in a quarter of the time (12 s/view) of the standard protocol, with preserved diagnostic accuracy. We now aim to establish the lower limit of radioactivity that can be administered to patients and the minimum acquisition time in SPECT MPI using an IQ SPECT protocol, while preserving diagnostic accuracy. Methods: An anthropomorphic cardiac phantom was used to acquire clinical rest scans with a simulated in vivo distribution of 99m Tc-tetrofosmin at full dose (740 MBq) and at doses equal to 50%, 25%, and 18%. For each dose, 2 sets of images were acquired, with and without a transmural defect (TD). Variable acquisition times were also used for each dose. We analyzed raw data and reconstructed images, including no correction and correction for attenuation (AC), for scatter (SC), or for both (ACSC). Images were evaluated qualitatively and quantitatively in order to assess left ventricle (LV) wall thickness (full width at half maximum of the medial sections), TD, and cavity contrast in the LV wall. Data were compared across different acquisition times within the same dose and across doses with the same acquisition time. Results: Images were visually scored as very-good quality except those acquired with 4 s/view or less at 100% dose and 6 s/view or less with 50%, 25%, or 18% dose, due to falsepositive defects. LV wall thickness was not significantly different among all acquisitions. Cavity contrast remained unchanged within the same dose for all images and tended to be higher in AC and ACSC images. TD contrast remained unchanged within the same dose for all images. In SC and no-correction images, contrast was constant for all doses. AC images had significantly higher TD contrast values, and ACSC images showed a drop in TD contrast for a 50% dose. Conclusion: IQ SPECT effectively preserved both image quality and quantitative measurements with reduced acquisition time or administered dose in a phantom study. These findings suggest that approximately one eighth of the time, compared with standard protocols with a full dose, or a lower dose at an acquisition time of 12 s/view can be applied in MPI without the loss of diagnostic accuracy.