Myocardial Fibrosis: Emerging Target for Cardiac Molecular Imaging and Opportunity for Image-Guided Therapy.

Myocardial fibrosis is a major contributor to the development and progression of heart failure. Significant progress in the understanding of its pathobiology has led to the introduction and preclinical testing of multiple highly specific antifibrotic therapies. Because the mechanisms of fibrosis are highly dynamic, and because the involved cell populations are heterogeneous and plastic, there is increasing emphasis that any therapy directed specifically against myocardial fibrosis will require personalization and guidance by equally specific diagnostic testing for successful clinical translation. Noninvasive imaging techniques have undergone significant progress and provide increasingly specific information about the quantity, quality, and activity of myocardial fibrosis. Cardiac MRI can precisely map the extracellular space of the myocardium, whereas nuclear imaging characterizes activated fibroblasts and immune cells as the cellular components contributing to fibrosis. Existing techniques may be used in complementarity to provide the imaging biomarkers needed for the success of novel targeted therapies. This review provides a road map on how progress in basic fibrosis research, antifibrotic drug development, and high-end noninvasive imaging may come together to facilitate the success of fibrosis-directed cardiovascular medicine.

Multicenter Evaluation of the Feasibility of Clinical Implementation of SPECT Myocardial Blood Flow Measurement: Intersite Variability and Imaging Time.

BACKGROUND: Single-center studies have shown that single photon emission computed tomography myocardial blood flow (MBF) measurement is accurate compared with MBF measured with microspheres in a porcine model, positron emission tomography, and angiography. Clinical implementation requires consistency across multiple sites. The study goal is to determine the intersite processing repeatability of single photon emission computed tomography MBF and the additional camera time required. METHODS: Five sites (Canada, Italy, Japan, Germany, and Singapore) each acquired 25 to 35 MBF studies at rest and with pharmacological stress using technetium-99m-tetrofosmin on a pinhole-collimated cadmium-zinc-telluride-based cardiac single photon emission computed tomography camera with standardized list-mode imaging and processing protocols. Patients had intermediate to high pretest probability of coronary artery disease. MBF was measured locally and at a core laboratory using commercially available software. The time a room was occupied for an MBF study was compared with that for a standard rest/stress myocardial perfusion study. RESULTS: With motion correction, the overall correlation in MBF between core laboratory and local site was 0.93 (range, 0.87-0.97) at rest, 0.90 (range, 0.84-0.96) at stress, and 0.84 (range, 0.70-0.92) for myocardial flow reserve. The local-to-core difference in global MBF (bias-MBF) was 5.4% (-3.8% to 14.8%; median [interquartile range]) at rest and 5.4% (-6.2% to 19.4%) at stress. Between the 5 sites, bias-MBF ranged from -1.6% to 11.0% at rest and from -1.9% to 16.3% at stress; the interquartile range in bias-MBF was between 9.3% (4.8%-14.0%) and 22.3% (-10.3% to 12.0%) at rest and between 17.0% (-11.3% to 5.6%) and 33.3% (-10.4% to 22.9%) at stress and was not significantly different between most sites. Both bias and interquartile range were like previously reported interobserver variability and less than the SD of the test-retest difference of 30%. The overall difference in myocardial flow reserve was 1.52% (-10.6% to 11.3%). There were no significant differences between with and without motion correction. The average additional acquisition time varied between sites from 44 to 79 minutes. CONCLUSIONS: The average bias-MBF and bias-MFR values were small with standard deviations substantially less than the test-retest variability. This demonstrates that MBF can be measured consistently across multiple sites and further supports that this technique can be reliably implemented. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03427749.

Total-Body Positron Emission Tomography: Adding New Perspectives to Cardiovascular Research.

The recent advent of positron emission tomography (PET) scanners that can image the entire human body opens up intriguing possibilities for cardiovascular research and future clinical applications. These new systems permit radiotracer kinetics to be measured in all organs simultaneously. They are particularly well suited to study cardiovascular disease and its effects on the entire body. They could also play a role in quantitatively measuring physiologic, metabolic, and immunologic responses in healthy individuals to a variety of stressors and lifestyle interventions, and may ultimately be instrumental for evaluating novel therapeutic agents and their molecular effects across different tissues. In this review, we summarize recent progress in PET technology and methodology, discuss several emerging cardiovascular applications for total-body PET, and place this in the context of multiorgan and systems medicine. Finally, we discuss opportunities that will be enabled by the technology, while also pointing to some of the challenges that still need to be addressed.

Molecular Imaging of Myocardial Fibroblast Activation in Patients with Advanced Aortic Stenosis Before Transcatheter Aortic Valve Replacement: A Pilot Study.

Using multimodal imaging, we investigated the extent and functional correlates of myocardial fibroblast activation in patients with aortic stenosis (AS) scheduled for transcatheter aortic valve replacement (TAVR). AS may cause myocardial fibrosis, which is associated with disease progression and may limit response to TAVR. Novel radiopharmaceuticals identify upregulation of fibroblast activation protein (FAP) as a cellular substrate of cardiac profibrotic activity. Methods: Twenty-three AS patients underwent 68Ga-FAP inhibitor 46 (68Ga-FAPI) PET, cardiac MRI, and echocardiography within 1-3 d before TAVR. Imaging parameters were correlated and then were integrated with clinical and blood biomarkers. Control cohorts of subjects without a history of cardiac disease and with (n = 5) and without (n = 9) arterial hypertension were compared with matched AS subgroups. Results: Myocardial FAP volume varied significantly among AS subjects (range, 1.54-138 cm3, mean ± SD, 42.2 ± 35.6 cm3) and was significantly higher than in controls with (7.42 ± 8.56 cm3, P = 0.007) and without (2.90 ± 6.67 cm3; P < 0.001) hypertension. FAP volume correlated with N-terminal prohormone of brain natriuretic peptide (r = 0.58, P = 0.005), left ventricular ejection fraction (r = -0.58, P = 0.02), mass (r = 0.47, P = 0.03), and global longitudinal strain (r = 0.55, P = 0.01) but not with cardiac MRI T1 (spin-lattice relaxation time) and extracellular volume (P = not statistically significant). In-hospital improvement in left ventricular ejection fraction after TAVR correlated with pre-TAVR FAP volume (r = 0.440, P = 0.035), N-terminal prohormone of brain natriuretic peptide, and strain but not with other imaging parameters. Conclusion: FAP-targeted PET identifies varying degrees of left ventricular fibroblast activation in TAVR candidates with advanced AS. 68Ga-FAPI signal does not match other imaging parameters, generating the hypothesis that it may become useful as a tool for personalized selection of optimal TAVR candidates.

Cardiac Applications of Fibroblast Activation Protein Imaging.

Several promising applications of cardiac molecular fibroblast activation protein (FAP) imaging are emerging. Myocardial fibrosis plays a key role in the complex process of cardiac remodeling and can lead to adverse clinical outcomes such as left ventricular dysfunction, propensity to arrhythmias, and reduction of perfusion. If fibrosis becomes irreversible, patients can develop heart failure. Therefore identification and early fibrosis treatment is highly warranted. FAP-targeted imaging enables new insights into pathogenesis and treatment response in various cardiac diseases such as myocardial infarction, heart failure or systemic diseases being a new selective biomarker.

Nuclear Methods for Immune Cell Imaging: Bridging Molecular Imaging and Individualized Medicine.

Inflammation is a key mechanistic contributor to the progression of cardiovascular disease, from atherosclerosis through ischemic injury and overt heart failure. Recent evidence has identified specific roles of immune cell subpopulations in cardiac pathogenesis that diverges between individual patients. Nuclear imaging approaches facilitate noninvasive and serial quantification of inflammation severity, offering the opportunity to predict eventual outcome, stratify patient risk, and guide novel targeted molecular therapies against specific leukocyte subpopulations. Here, we will discuss the established and emerging nuclear imaging methods to label and track exogenous and endogenous immune cells, with a particular focus on clinical situations in which targeted molecular inflammation imaging would be advantageous. The expanding options for imaging inflammation provide the foundation to bridge between molecular imaging and individual therapy.

Giant cell myocarditis after first dose of BNT162b2 - a case report.

Herein we report the case of a young man, admitted to the Department of Cardiology and Angiology at Hannover Medical School with shortness of breath and elevated troponin. Few weeks earlier the patient received the first dose of BioNTech's mRNA vaccine (Comirnaty, BNT162b2). After diagnostic work-up revealed giant cell myocarditis, the patient received immunosuppressive therapy. In the present context of myocarditis after mRNA vaccination we discuss this rare aetiology and the patient's treatment strategy in the light of current recommendations.

[Clinical use of Cardiac Nuclear Medicine in Germany]. / Nuklearmedizinische Funktionsdiagnostik in der Kardiologie.

Cardiac nuclear medicine comprises various diagnostic techniques using radiopharmaceuticals for functional imaging in vivo. This article provides an overview of current clinical use of cardiac imaging in nuclear medicine in Germany: Myocardial perfusion imaging using SPECT is a well-established noninvasive tool to semi-quantitatively measure left ventricular myocardial perfusion. Ischemia and chronic myocardial scars can be idenified with a high diagnostic accuracy. Gated SPECT enables measuring left ventricular function. With new dedicated solid-state camera systems examinations have become faster and better while radiation exposure has been minimized. These new camera systems allow quantitative calculations of myocardial blood flow, which will further improve diagnostic accuracy.For patients with severe chronic coronary artery disease and myocardial dysfunction analyzing myocardial viability is crucial for guiding therpeutic decisions. For detection of hibernating myocardium and its differentiation from scar tissue, two nuclear cardiac methods are combined: Rest myocardial perfusion imaging detects perfusion defects and cardiac 18F-FDG-PET/CT detects glucose metabolism in the hypoperfused area. As long as glucose metabolism is intact therapeutic interventions can be beneficial.In general 18F-FDG-PET/CT allows visualization and quantification of celluar glucose metabolism in oncologic and inflammatory processes. For analysis of cardiac inflammation (e. g. endocarditis or sarcoidosis) a no-carb and high-protein diet is needed at leat 24 hours prior to imaging in order to suppress the physiologic myocardial glucose metabolism. Then, specific inflammatory tracer uptake can be assessed.Cardiac amyloidosis is a rare but dangerous condition. With a specific amyloidosis scintigraphy (bone scintigraphy), cardiac ATTR-amyloidosis can be diagnosed with high accuracy. A potenitally harmful myocardial biopsy often is not needed any more and specific therapy can be initiated.In summary, diagnostic methods in cardiac nuclear medicine non-invasively allow visualization and function analysis of biological processes and are essential for diagnosis finding and therapy guidance. The continuous advancement of diagnostic tools makes nuclear cardiology a highly relevant and interesting field.

Intracoronary Application of Super-Saturated Oxygen to Reduce Infarct Size Following Myocardial Infarction.

Optimal medical therapy for secondary prevention following acute myocardial infarction reduces non-fatal ischaemic events. Intensive antithrombotic or lipid-lowering approaches have failed to significantly lower mortality. In the past, reduction of infarct size in patients undergoing primary percutaneous revascularisation for acute myocardial infarction had been considered as a surrogate outcome marker. However, infarct size measured by magnetic resonance imaging or SPECT is strongly associated with all-cause mortality and hospitalization for heart failure within the first year after an acute myocardial infarction. Intracoronary administration of super-saturated oxygen (SSO2) immediately after revascularisation is an approach that can be used to reduce infarct size and, therefore, improve cardiovascular outcome in patients with acute myocardial infarction. In this article, we describe the modulation of pathophysiology by SSO2, review the existing trial data and present our first impressions with the technique in real clinical practice.

Cardiac Fibroblast Activation in Patients Early After Acute Myocardial Infarction: Integration with MR Tissue Characterization and Subsequent Functional Outcome.

After acute myocardial infarction (AMI), fibroblast activation protein (FAP) upregulation exceeds the infarct region. We sought further insights into the physiologic relevance by correlating FAP-targeted PET with tissue characteristics from cardiac MRI (CMR) and functional outcome. Methods: Thirty-five patients underwent CMR, perfusion SPECT, and 68Ga-FAP inhibitor (FAPI)-46 PET/CT within 11 d after AMI. Infarct size was determined from SPECT by comparison to a reference database. For PET, regional SUVs and isocontour volumes of interest determined the extent of cardiac FAP upregulation (FAP volume). CMR yielded functional parameters, area of injury (late gadolinium enhancement [LGE]) and T1/T2 mapping. Follow-up was available from echocardiography or CMR after 139.5 d (interquartile range, 80.5-188.25 d) (n = 14). Results: The area of FAP upregulation was significantly larger than the SPECT perfusion defect size (58% ± 15% vs. 23% ± 17%, P < 0.001) and infarct area by LGE (28% ± 11%, P < 0.001). FAP volume significantly correlated with CMR parameters at baseline (all P < 0.001): infarct area (r = 0.58), left ventricle (LV) mass (r = 0.69), end-systolic volume (r = 0.62), and end-diastolic volume (r = 0.57). Segmental analysis revealed FAP upregulation in 308 of 496 myocardial segments (62%). Significant LGE was found in only 56% of FAP-positive segments, elevated T1 in 74%, and elevated T2 in 68%. Fourteen percent (44/308) of FAP-positive segments exhibited neither prolonged T1 or T2 nor significant LGE. Of note, FAP volume correlated only weakly with simultaneously measured LV ejection fraction at baseline (r = -0.32, P = 0.07), whereas there was a significant inverse correlation with LV ejection fraction obtained at later follow-up (r = -0.58, P = 0.007). Conclusion: Early after AMI and reperfusion therapy, activation of fibroblasts markedly exceeds the hypoperfused infarct region and involves noninfarcted myocardium. The 68Ga-FAPI PET signal does not match regional myocardial tissue characteristics as defined by CMR but is predictive of the evolution of ventricular dysfunction. FAP-targeted imaging may provide a novel biomarker of LV remodeling that is complementary to existing techniques.

Molecular imaging of inflammation crosstalk along the cardio-renal axis following acute myocardial infarction.

Rationale: Acute myocardial infarction (MI) triggers a systemic inflammatory response including crosstalk along the heart-kidney axis. We employed radionuclide-based inflammation-targeted whole-body molecular imaging to identify potential cardio-renal crosstalk after MI in a translational setup. Methods: Serial whole-body positron emission tomography (PET) with the specific CXCR4 ligand 68Ga-Pentixafor was performed after MI in mice. Tracer retention in kidneys and heart was compared to hematopoietic organs to evaluate systemic inflammation, validated by ex vivo analysis and correlated with progressive contractile dysfunction. Additionally, 96 patients underwent 68Ga-Pentixafor PET within the first week after MI, for systems-based image analysis and to determine prognostic value for adverse renal outcome. Results: In mice, transient myocardial CXCR4 upregulation occurred early after MI. Cardiac and renal PET signal directly correlated over the time course (r = 0.62, p < 0.0001), suggesting an inflammatory link between organs. Ex-vivo autoradiography (r = 0.9, p < 0.01) and CD68 immunostaining indicated signal localization to inflammatory cell content. Renal signal at 7d was inversely proportional to left ventricular ejection fraction at 6 weeks after MI (r = -0.79, p < 0.01). In patients, renal CXCR4 signal also correlated with signal from infarct (r = 0.25, p < 0.05) and remote myocardium (r = 0.39, p < 0.0001). Glomerular filtration rate (GFR) was available in 48/96 (50%) during follow-up. Worsening of renal function (GFR loss >5 mL/min/1.73m2), occurred a mean 80.5 days after MI in 16/48 (33.3%). Kaplan-Meier analysis revealed adverse renal outcome for patients with elevated remote myocardial CXCR4 signal (p < 0.05). Multivariate Cox analysis confirmed an independent predictive value (relative to baseline GFR, LVEF, infarct size; HR, 5.27). Conclusion: Systems-based CXCR4-targeted molecular imaging identifies inflammatory crosstalk along the cardio-renal axis early after MI.

Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4.

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.

Gallbladder Visualization in Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE: A Potential Mimicker of Hepatic Metastases.

Gallbladder visualization represents a rare incidental finding when using somatostatin receptor-targeted SPECT radiopharmaceuticals such as In-octreotide. We present the case of a 30-year-old man with pseudomyogenic hemangioendothelioma who underwent Ga-DOTATATE PET/CT for restaging of metastatic disease and subsequent treatment with peptide receptor radionuclide therapy with Lu-DOTATATE. Posttherapeutic SPECT/CT, but not pretherapeutic or posttherapeutic PET/CT, showed gallbladder visualization, evidencing Lu-DOTATATE excretion into the bile. This case highlights that biliary Lu-DOTATATE excretion may represent a rare mimicker of hepatic metastases and emphasizes the role SPECT/CT for precise anatomical correlation to avoid misinterpretation.

The Changing Face of Nuclear Cardiology: Guiding Cardiovascular Care Toward Molecular Medicine.

Radionuclide imaging of myocardial perfusion, function, and viability has been established for decades and remains a robust, evidence-based and broadly available means for clinical workup and therapeutic guidance in ischemic heart disease. Yet, powerful alternative modalities have emerged for this purpose, and their growth has resulted in increasing competition. But the potential of the tracer principle goes beyond the assessment of physiology and function, toward the interrogation of biology and molecular pathways. This is a unique selling point of radionuclide imaging, which has been underrecognized in cardiovascular medicine until recently. Now, molecular imaging methods for the detection of myocardial infiltration, device infection, and cardiovascular inflammation are successfully gaining clinical acceptance. This is further strengthened by the symbiotic quest of cardiac imaging and therapy for an increasing implementation of molecule-targeted procedures, in which specific therapeutic interventions require specific diagnostic guidance toward the most suitable candidates. This review will summarize the current advent of clinical cardiovascular molecular imaging and highlight its transformative contribution to the evolution of cardiovascular therapy beyond mechanical interventions and broad blockbuster medication, toward a future of novel, individualized molecule-targeted and molecular imaging-guided therapies.

A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry.

AIMS: Clinical presentation of takotsubo syndrome (TTS) mimics acute coronary syndrome (ACS) and does not allow differentiation. We aimed to develop a clinical score to estimate the probability of TTS and to distinguish TTS from ACS in the acute stage. METHODS AND RESULTS: Patients with TTS were recruited from the International Takotsubo Registry ( www.takotsubo-registry.com) and ACS patients from the leading hospital in Zurich. A multiple logistic regression for the presence of TTS was performed in a derivation cohort (TTS, n = 218; ACS, n = 436). The best model was selected and formed a score (InterTAK Diagnostic Score) with seven variables, and each was assigned a score value: female sex 25, emotional trigger 24, physical trigger 13, absence of ST-segment depression (except in lead aVR) 12, psychiatric disorders 11, neurologic disorders 9, and QTc prolongation 6 points. The area under the curve (AUC) for the resulting score was 0.971 [95% confidence interval (CI) 0.96-0.98] and using a cut-off value of 40 score points, sensitivity was 89% and specificity 91%. When patients with a score of ≥50 were diagnosed as TTS, nearly 95% of TTS patients were correctly diagnosed. When patients with a score ≤31 were diagnosed as ACS, ∼95% of ACS patients were diagnosed correctly. The score was subsequently validated in an independent validation cohort (TTS, n = 173; ACS, n = 226), resulting in a score AUC of 0.901 (95% CI 0.87-0.93). CONCLUSION: The InterTAK Diagnostic Score estimates the probability of the presence of TTS and is able to distinguish TTS from ACS with a high sensitivity and specificity. TRIAL REGISTRATION: NCT0194762.

Safety and efficacy profile of bioresorbable-polylactide-polymer-biolimus-A9-eluting stents versus durable-polymer-everolimus- and zotarolimus-eluting stents in patients with acute coronary syndrome.

BACKGROUND: Comparative data on long-term safety and efficacy of bioresorbable-polymer-BES versus durable-polymer-EES/ZES in ACS setting have hitherto been lacking. We sought to assess the safety and efficacy of bioresorbable-polymer-biolimus-A9-eluting stents (BES) compared with thin-strut-durable-polymer-everolimus- and zotarolimus-eluting stents (EES/ZES) in patients with acute coronary syndrome (ACS) undergoing PCI. METHODS AND RESULTS: Between 2007 and 2012, 1,547 patients were implanted with new-generation drug-eluting stents (DES). Out of these, 369 received BES and 1,178 EES/ZES. The primary endpoint was probable/definite stent thrombosis (ST) while the secondary endpoint was a composite of all-cause death, myocardial infarction (MI), target vessel revascularization (TVR) and definite ST up to 5 years. As stent assignment was not random, we performed a propensity score matching (PSM), with 1:3 ratio, to account for potential confounders. Primary analysis demonstrated no significant differences between both groups for the primary endpoint of ST (BES vs. EES/ZES: 1.6% vs. 1.9%; mean-event-time = 1,797 days vs. 1,795 days, respectively; P = 0.75) and composite safety endpoint (BES vs. EES/ZES: 12.5% vs. 12.9%; mean-event-time = 1,631 days vs. 1,620 days, respectively; P = 0.88). Results regarding the 5-year-ST- and safety endpoint remained non-significant after PSM (P = 0.85, P = 0.56; respectively). After stratification based on cardiovascular risk, no difference regarding ST and composite outcome measure has been documented between both stent groups in high-risk- and low-risk patients. The type of stent did neither predict ST (HR 1.11, 95%CI 0.45-2.74, P = 0.82) nor composite safety endpoint (HR 0.93, 95%CI 0.67-1.30, P = 0.69). CONCLUSIONS: Long-term safety and efficacy of bioresorbable-polymer-BES and durable-polymer-EES/ZES appear comparable in patients with ACS. © 2016 Wiley Periodicals, Inc.