Myocardial Viability Research Articles

The Role of Coronary Imaging in Chronic Total Occlusions: Applications and Future Possibilities.

Chronic total occlusions (CTOs) represent a challenging scenario in coronary artery disease (CAD). The prevalence of CTOS in patients undergoing coronary angiography underscores the need for effective diagnostic and therapeutic strategies. Coronary angiography, while essential, offers limited insights into lesion morphology, vessel course, and myocardial viability. In contrast, coronary imaging techniques-including optical coherence tomography (OCT), intravascular ultrasound (IVUS), and coronary computed tomography angiography (CCTA)-provide comprehensive insights for each stage of CTO percutaneous coronary intervention (PCI). OCT facilitates the assessment of plaque morphology and stent optimization, despite low evidence and several limitations in CTO-PCI. IVUS offers deeper penetration, allowing managing proximal cap scenarios and guiding subintimal navigation. CCTA provides a non-invasive, three-dimensional view of coronary anatomy, enabling the precise evaluation of myocardial mass at risk and detailed procedural planning. Despite their individual limitations, these imaging modalities have enhanced the success rates of CTO-PCI, thus reducing procedural and long-term complications and improving patient outcomes. The future of CTO management lies in further technological advancements, including hybrid imaging, artificial intelligence (AI) integration, and improved fusion imaging. These innovations promise to refine procedural precision and personalize interventions, ultimately improving the care of patients with complex coronary artery disease.

A Novel Approach to Identifying Hibernating Myocardium Using Radiomics-Based Machine Learning.

Background To assess the feasibility of a machine learning (ML) approach using radiomics features of perfusion defects on rest myocardial perfusion imaging (MPI) to detect the presence of hibernating myocardium. Methodology Data of patients who underwent 99mTc-sestamibi MPI and 18F-FDG PET/CT for myocardial viability assessment were retrieved. Rest MPI data were processed on ECToolbox, and polar maps were saved using theNFile PMap tool. The reference standard for defining hibernating myocardium was the presence of mismatched perfusion-metabolism defect with impaired myocardial contractility at rest. Perfusion defects on the polar maps were delineated with regions of interest (ROIs) after spatial resampling and intensity discretization. Replicable random sampling allocated 80% (257) of the perfusion defects of the patients from January 2017 to September 2022 to the training set and the remaining 20% (64) to the validation set. An independent dataset of perfusion defects from 29 consecutive patients from October 2022 to January 2023 was used as the testing set for model evaluation. One hundred ten first and second-order texture features were extracted for each ROI. After feature normalization and imputation, 14 best-ranked features were selected using a multistep feature selection process including the Logistic Regression and Fast Correlation-Based Filter. Thirteen supervised ML algorithms were trained with stratified five-fold cross-validation on the training set and validated on the validation set. The ML algorithms with a Log Loss of <0.688 and <0.672 in the cross-validation and validation steps were evaluated on the testing set. Performance matrices of the algorithms assessed included area under the curve (AUC), classification accuracy (CA), F1 score, precision, recall, and specificity. To provide transparency and interpretability, SHapley Additive exPlanations (SHAP) values were assessed and depicted as beeswarm plots. Results Two hundred thirty-nine patients (214 males; mean age 56 ± 11 years) were enrolled in the study. There were 371 perfusion defects (321 in the training and validation sets; 50 in the testing set). Based on the reference standard, 168 perfusion defects had hibernating myocardium (139 in the training and validation sets; 29 in the testing set). On cross-validation, six ML algorithms with Log Loss <0.688 had AUC >0.800. On validation, 10 ML algorithms had a Log Loss value <0.672, among which six had AUC >0.800. On model evaluation of the selected models on the unseen testing set, nine ML models had AUC >0.800 with Gradient Boosting Random Forest (xgboost) [GB RF (xgboost)] achieving the highest AUC of 0.860 and could detect the presence of hibernating myocardium in 21/29 (72.4%) perfusion defects with a precision of 87.5% (21/24), specificity 85.7% (18/21), CA 78.0% (39/50) and F1 Score 0.792. Four models depicted a clear pattern of model interpretability based on the beeswarm SHAP plots. These were GB RF (xgboost), GB (scikit-learn), GB (xgboost), and Random Forest. Conclusion Our study demonstrates the potential of ML in detecting hibernating myocardium using radiomics features extracted from perfusion defects on rest MPI images. This proof-of-concept underscores the notion that radiomics features capture nuanced information beyond what is perceptible to the human eye, offering promising avenues for improved myocardial viability assessment.

Image Quality of Cardiac Silicon Photomultiplier PET/CT Using an Infant Phantom of Extremely Low Birth Weight.

The lack of pediatrics-specific equipment for nuclear medicine imaging has resulted in insufficient diagnostic information for newborns, especially low-birth-weight infants. Although PET offers high spatial resolution and low radiation exposure, its use in newborns is limited. This study investigated the feasibility of cardiac PET imaging using the latest silicon photomultiplier (SiPM) PET technology in infants of extremely low birth weight (ELBW) using a phantom model. Methods: The study used a phantom model representing a 500-g ELBW infant with brain, cardiac, liver, and lung tissues. The cardiac tissue included a 3-mm-thick defect mimicking myocardial infarction. Organ tracer concentrations were calculated assuming 18F-FDG myocardial viability scans and 18F-flurpiridaz myocardial perfusion scans and were added to the phantom organs. Imaging was performed using an SiPM PET/CT scanner with a 5-min acquisition. The data acquired in list mode were reconstructed using 3-dimensional ordered-subsets expectation maximization with varying iterations. Image evaluation was based on the depiction of the myocardial defect compared with normal myocardial accumulation. Results: Increasing the number of iterations improved the contrast of the myocardial defect for both tracers, with 18F-flurpiridaz showing higher contrast than 18F-FDG. However, even at 50 iterations, both tracers overestimated the defect accumulation. A bull's-eye image can display the flow metabolism mismatch using images from both tracers. Conclusion: SiPM PET enabled cardiac PET imaging in a 500-g ELBW phantom with a 1-g heart. However, there were limitations in adequately depicting these defects. Considering the image quality and defect contrast,18F-flurpiridaz appears more desirable than 18F-FDG if only one of the two can be used.

Current and Future Roles of Glycoprotein IIb-IIIa Inhibitors in Primary Angioplasty for ST-Segment Elevation Myocardial Infarction.

Acute myocardial infarction still represents the major cause of mortality in high-income countries. Therefore, considerable efforts have been focused on the treatment of myocardial infarctions in the acute and long-term phase, with special attention being paid to reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite the successful mechanical recanalization of the epicardial conduit, a substantial percentage of patients still experience poor myocardial reperfusion or acute/subacute in-stent thrombosis. Due the delayed onset of action of currently available oral antiplatelet therapies, glycoprotein (GP) IIb-IIIa inhibitors could be expected to improve clinical outcomes, especially when administrated in the early phase of the infarction, due to the larger platelet composition of fresh thrombi, the dynamic nature of early thrombi, and the larger amount of viable myocardium existing in the early, as compared to a delayed, phase. Considerable evidence has accumulated regarding the benefits from GP IIb-IIIa inhibitors on mortality, especially among high-risk patients and when administered as an upstream strategy. Therefore, based on currently available data, GP IIb-IIIa inhibitors can be considered when the drug can be administered within the first 3 h of symptom onset and among high-risk patients (e.g., those with advanced Killip class or an anterior myocardial infarction). Even though it is not universally accepted, in our opinion, this strategy should be implemented in a pre-hospital setting (in an ambulance) or as soon as possible when arriving at the hospital (at the Emergency Room or Coronary Care Unit, irrespective of whether they are in spoke or hub hospitals). A new, second-generation GP IIb-IIIa inhibitor (zalunfiban) appears to be highly suitable as a pre-hospital pharmacological facilitation strategy at the time of first medical contact due to its favourable features, including its simple subcutaneous administration, rapid onset of action (15 min), and limited time of action (with a half-life of ~1 h), which is likely to minimize the risk of bleeding. The ongoing CELEBRATE trial, including 2499 STEMI patients, may potentially provide compelling data to support the upstream treatment of STEMI patients undergoing mechanical reperfusion. In fact, although the current therapeutic target of increased rates of timely reperfusion has been achieved, the future goal in myocardial infarction treatment should be to achieve the most rapid reperfusion prior to primary percutaneous coronary intervention, thus further minimizing myocardial damage, or, in some cases, even preventing it completely, and improving survival.

Whole-Heart Histological and Electroanatomic Assessment of Postinfarction Cardiac Magnetic Resonance Imaging Scar and Conducting Channels.

Cardiac magnetic resonance imaging (CMR)-defined ventricular scar and anatomic conduction channels (CMR-CCs) offer promise in delineating ventricular tachycardia substrate. No studies have validated channels with coregistered histology, nor have they ascertained the histological characteristics of deceleration zones (DZs) within these channels. We aimed to validate CMR scar and CMR-CCs with whole-heart histology and electroanatomic mapping in a postinfarction model. Five sheep underwent anteroseptal infarction. CMR (116±20 days post infarct) was postprocessed using ADAS-3D, varying pixel intensity thresholds (5545, 6040, 6535, and 7030). DZs were identified by electroanatomic mapping (129±12 days post infarct). Explanted hearts were sectioned and stained with Picrosirius red, and whole-heart histopathologic shells were generated. Scar topography as well as percentage fibrosis, adiposity, and remaining viable myocardium within 3 mm histological biopsies and within CMR-CCs were determined. Using the standard 6040 thresholding, CMR had 83.8% accuracy for identifying histological scar in the endocardium (κ, 0.666) and 61.4% in the epicardium (κ, 0.276). Thirty-seven CMR-CCs were identified by varying thresholding; 23 (62%) were unique. DZs colocalized to 19 of 23 (83%) CMR-CCs. Twenty (87%) CMR-CCs were histologically confirmed. Within-channel histological fibrosis did not differ by the presence of DZs (P=0.242). Within-channel histological adiposity was significantly higher at sites with versus without DZs (24.1% versus 8.3%; P<0.001). Postprocessed CMR-derived scars and channels were validated by histology and electroanatomic mapping. Regions of CMR-CCs at sites of DZs had higher adiposity but similar fibrosis than regions without DZs, suggesting that lipomatous metaplasia may contribute to arrhythmogenicity of postinfarction scar.

Snhg14/miR-181a-5p axis-mediated “M1” macrophages aggravate LPS-induced myocardial cell injury

An increasing number of studies have suggested that macrophages participate in sepsis-induced myocardial injury. Our study highlights the function and mechanism of the lncRNA Snhg14 in “M1” polarized macrophage-mediated myocardial cell damage. Lipopolysaccharide (LPS) was used to treat H9c2 cells to construct an in vitro myocardial injury model. M1 and M2 polarization of RAW264.7 cells were induced and the exosomes were obtained from the supernatant through ultracentrifugation. Moreover, cecal ligation and puncture (CLP) surgery was implemented to establish a mouse sepsis-induced myocardial injury model, and Snhg14 was knocked down with sh-Snhg14. The results showed that the conditioned medium (CM) and the exosomes (Exo) of M1 macrophages substantially augmented LPS-induced apoptosis and oxidative stress in myocardial cells. Notably, M1-CM and M1-Exo contributed to nearly 50 % of myocardial cell viability decline. Snhg14 was highly expressed in M1 macrophages and exosomes derived from M1-MΦ (M1-Exo). Snhg14 overexpression aggravated myocardial cell damage and increased 10 to 50 times expression of proinflammatory cytokines in MΦ. Snhg14 knockdown reversed M1-Exo-mediated myocardial cell damage and inhibited the production of proinflammatory cytokines (50 %–75 % decline) of MΦ. Moreover, Snhg14 targeted and inhibited miR-181a-5p expression. miR-181a-5p upregulation partly reversed Snhg4 overexpression-mediated myocardial cell damage and MΦ activation. In vivo, sh-Snhg14 dramatically ameliorated cardiac damage in septic mice by enhancing miR-181a-5p and inhibiting the HMGB1/NF-κB pathway. In conclusion, “M1” macrophage-derived exosomal Snhg14 aggravates myocardial cell damage by modulating the miR-181a-5p/HMGB1/NF-κB pathway.

Characterization of cardiac resynchronization therapy response through machine learning and personalized models

Introduction: The characterization and selection of heart failure (HF) patients for cardiac resynchronization therapy (CRT) remain challenging, with around 30% non-responder rate despite following current guidelines. This study aims to propose a novel hybrid approach, integrating machine-learning and personalized models, to identify explainable phenogroups of HF patients and predict their CRT response. Methods:The paper proposes the creation of a complete personalized model population based on preoperative CRT patient strain curves. Based on the parameters and features extracted from these personalized models, phenotypes of patients are identified thanks to a clustering algorithm and a random forest classification is provided. Results:A close match was observed between the 162 experimental and simulated myocardial strain curves, with a mean RMSE of 4.48% (±1.08) for the 162 patients. Five phenogroups of personalized models were identified from the clustering, with response rates ranging from 52% to 94%. The classification results show a mean area under the curves (AUC) of 0.86 ± 0.06 and provided a feature importance analysis with 22 features selected. Results show both regional myocardial contractility (from 22.5% to 33.0%), tissue viability and electrical activation delays importance on CRT response for each HF patient (from 55.8 ms to 88.4 ms). Discussion:The patient-specific model parameters’ analysis provides an explainable interpretation of HF patient phenogroups in relation to physiological mechanisms that seem predictive of the CRT response. These novel combined approaches appear as promising tools to improve understanding of LV mechanical dyssynchrony for HF patient characterization and CRT selection.

Protective effects of mesenchymal stem cells-derived extracellular vesicles against ischemia-reperfusion injury of hearts donated after circulatory death: Preliminary study in a pig model

IntroductionInsufficient supply of cardiac grafts represents a severe obstacle in heart transplantation. Donation after Circulatory Death (DCD), in addition to conventional donation after brain death, is one promising option to overcome the organ shortage. However, DCD organs undergo an inevitable more extended period of warm unprotected ischemia between circulatory arrest and graft procurement. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have shown remarkable protective effects against ischemia-reperfusion injury. Thus, we aimed to enhance grafts preservation from DCD donors, through treatment with MSC-EVs. MethodsFemale pigs were euthanized by barbiturate overdose and after 20 min of a flat EKG, the chest was opened, the heart harvested and subsequently connected to an extracorporeal perfusion machine. MSC-EVs, isolated by ion exchange chromatography, were added to the perfusion solution (1×1011 particles) and the heart was perfused for 2 h. Then, heart tissue biopsies were taken to assess histological changes, mitochondrial morphology, antioxidant enzyme activity and inflammation mediators’ expression. Biochemical parameters of myocardial viability were assessed in the perfusate. ResultsThe treatment with MSC-EVs significantly prevented mitochondria swelling, mitochondrial cristae loss and oxidative stress in cardiac tissue. The protective effect of MSC-EVs was confirmed by the delayed increase of the cardiac-specific enzymes CK and TnC in the perfusate and the reduction of caspase-3+ cells in tissue sections. ConclusionMSC-EVs improve graft quality by preserving the mitochondrial ultrastructure protecting the myocardium against oxidative stress, reducing apoptosis of cardiac cells and preventing the increase of pro-inflammatory cytokines.

Evaluation of Clinical Variables Affecting Myocardial Glucose Uptake in Cardiac FDG PET.

Cardiac 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG PET) is widely used to assess myocardial viability in patients with ischemic heart disease. While sufficient glucose uptake is a prerequisite for accurate interpretation of cardiac viability, there are a lack of data on which clinical variables have the most significant impact on myocardial glucose metabolism. Therefore, this study was designed to evaluate several clinical variables that could affect myocardial glucose metabolism. A total of 214 consecutive cases were retrospectively enrolled in this study. All subjects received 250 mg of acipimox and underwent glucose loading as preparation for cardiac FDG PET/CT. Three-dimensional regions of interest (ROIs) were drawn on PET/CT fusion images. Myocardial glucose uptake ratio (MGUR = SUVmax of LV myocardium/SUVmean of liver) was then calculated. Multiple clinical variables including body mass index (BMI), blood glucose levels at different times, administered insulin dosage, lipid profiles, and ejection fraction were measured and analyzed for correlation with myocardial glucose uptake. After dichotomizing the subjects based on a BMI of 25, each group's MGUR was compared. Myocardial uptake showed significant correlations with BMI (r = -0.162, p = 0.018), HbA1c (r = -0.150, p = 0.030), and triglyceride levels (r = -0.137, p = 0.046). No other clinical variables showed a significant correlation with myocardial glucose uptake. After multiple linear regression analysis, BMI (p = 0.032) and HbA1c (p = 0.050) showed a correlation with MGUR. In group analysis, after dividing patients based on BMI, the obese group showed significantly lower myocardial uptake than the non-obese group (3.8 ± 1.9 vs. 4.4 ± 2.1, p = 0.031). Among several clinical variables, BMI and HbA1c levels were related to myocardial glucose uptake. A prospective study would be needed to examine whether a protocol that additionally considers BMI and HbA1c levels is necessary for the current cardiac FDG PET protocol.

Automatic pipeline for segmentation of LV myocardium on quantitative MR T1 maps using deep learning model and computation of radial T1 and ECV values.

Native T1 mapping is a non-invasive technique used for early detection of diffused myocardial abnormalities, and it provides baseline tissue characterization. Post-contrast T1 mapping enhances tissue differentiation, enables extracellular volume (ECV) calculation, and improves myocardial viability assessment. Accurate and precise segmenting of the left ventricular (LV) myocardium on T1 maps is crucial for assessing myocardial tissue characteristics and diagnosing cardiovascular diseases (CVD). This study presents a deep learning (DL)-based pipeline for automatically segmenting LV myocardium on T1 maps and automatic computation of radial T1 and ECV values. The study employs a multicentric dataset consisting of retrospective multiparametric MRI data of 332 subjects to develop and assess the performance of the proposed method. The study compared DL architectures U-Net and Deep Res U-Net for LV myocardium segmentation, which achieved a dice similarity coefficient of 0.84 ±0.43 and 0.85 ±0.03, respectively. The dice similarity coefficients computed for radial sub-segmentation of the LV myocardium on basal, mid-cavity, and apical slices were 0.77 ±0.21, 0.81 ±0.17, and 0.61 ±0.14, respectively. The t-test performed between ground truth vs. predicted values of native T1, post-contrast T1, and ECV showed no statistically significant difference (p> 0.05) for any of the radial sub-segments. The proposed DL method leverages the use of quantitative T1 maps for automatic LV myocardium segmentation and accurately computing radial T1 and ECV values, highlighting its potential for assisting radiologists in objective cardiac assessment and, hence, in CVD diagnostics.

Tissue-Based Predictors of Impaired Right Ventricular Strain in Coronary Artery Disease: A Multicenter Stress Perfusion Study.

Right ventricular (RV) dysfunction is known to impact prognosis, but its determinants in coronary artery disease are poorly understood. Stress cardiac magnetic resonance (CMR) has been used to assess ischemia and infarction in relation to the left ventricle (LV); the impact of myocardial tissue properties on RV function is unknown. Vasodilator stress CMR was performed in patients with known coronary artery disease at 7 sites between May 2005 and October 2018. Myocardial infarction was identified on late gadolinium enhancement-CMR, and infarct transmurality was graded on a per-segment basis. Ischemia was assessed on stress CMR based on first-pass perfusion and localized by using segment partitions corresponding to cine and late gadolinium enhancement analyses. RV function was evaluated by CMR-feature tracking for primary analysis with a global longitudinal strain threshold of 20% used to define impaired RV strain (RVIS); secondary functional analysis via RV ejection fraction was also performed. A total of 2604 patients were studied, among whom RVIS was present in 461 patients (18%). The presence and magnitude of RVIS were strongly associated with LV dysfunction, irrespective of whether measured by LV ejection fraction or wall motion score (P<0.001 for all). Regarding tissue substrate, regions of ischemic and dysfunctional myocardium (ie, hibernating myocardium) and infarct size were each independently associated with RVIS (both P<0.001). During follow-up (median, 4.62 [interquartile range, 2.15-7.67] years), 555 deaths (21%) occurred. Kaplan-Meier analysis for patients stratified by presence and magnitude of RV dysfunction by global longitudinal strain and RV ejection fraction each demonstrated strong prognostic utility for all-cause mortality (P<0.001). RVIS conferred increased mortality risk (hazard ratio, 1.35 [95% CI, 1.11-1.66]; P=0.003) even after controlling for LV function, infarction, and ischemia. RVIS in patients with known coronary artery disease is associated with potentially reversible LV processes, including LV functional impairment due to ischemic and predominantly viable myocardium, which confers increased mortality risk independent of LV function and tissue substrate.

Comparative Analysis of Nitrate-Augmented MPI and FDG PET for Myocardial Viability Assessment

Comparative Analysis of Nitrate-Augmented MPI and FDG PET for Myocardial Viability Assessment

Review of Myocardial Ischemia, Scar, and Viability Estimation with Molecular Magnetic Resonance Imaging.

Cardiovascular diseases, particularly myocardial ischemia from coronary artery obstruction, remain a leading cause of global morbidity. This review explores cardiac molecular magnetic resonance imaging (mMRI) and other molecular imaging techniques for the evaluation of myocardial ischemia, scarring, and viability. mMRI imaging methods provide detailed information on myocardial ischemia, edema, and scar tissue using techniques like cine imaging, T1 and T2 mapping, and gadolinium-based contrast agents. These methods enable the precise assessment of the myocardial tissue properties, crucial in diagnosing and treating cardiovascular diseases. Advanced techniques, such as the T1ρ and RAFFn methods, might provide enhanced contrast and sensitivity for the detection of myocardial scarring without contrast agents. Molecular probes, including gadolinium-based and protein-targeted contrast agents, improve the detection of molecular changes, facilitating early diagnosis and personalized treatment. Integrating MRI with positron emission tomography (PET) combines the high spatial and temporal resolution with molecular and functional imaging. Recent advancements in mMRI and molecular imaging have changed the evaluation of myocardial ischemia, scarring, and viability. Despite significant progress, extensive research is needed to validate these techniques clinically and further develop imaging methods for better diagnostic and prognostic outcomes.

Acute ST elevation myocardial infarction (STEMI) in a patient with leptospirosis; a therapeutical dilemma – A case report

A 45-year-old previously healthy farmer was seen at the Emergency Department with ischemic type chest pain. He had a history of an acute febrile illness for four days. The ECG showed an acute anterior myocardial infarction. His laboratory investigations revealed thrombocytopenia, a raised serum creatinine level and significantly raised high-sensitive cardiac Troponin I. A provisional diagnosis of acute STEMI with co-existing leptospirosis was made. The patient was managed conservatively with antibiotics, statins, and aspirin. Neither thrombolysis nor primary coronary intervention was attempted due to high risk of bleeding. Diagnosis of leptospirosis was confirmed later by markedly elevated leptospira antibodies. After recovery, he underwent coronary angiogram which revealed a totally occluded left anterior descending artery and is awaiting myocardial viability assessment with dobutamine stress echocardiography before PCI. We report this uncommon presentation of acute myocardial infarction in a patient with leptospirosis, as it causes a considerable therapeutic dilemma especially in a resource-poor setting.

Coronary Angiography During Ex-Situ Heart Perfusion in a Porcine Model.

Heart transplantation is the gold standard treatment for advanced heart failure. The procurement of extended criteria donors (ECD) increases due to the current organ shortage. Coronary angiography is recommended in ECD at risk for coronary artery disease but is not systematically performed. These hearts are, therefore, either declined for transplant or procured without screening for coronary artery disease. Coronary angiography during normothermic ex-situ heart perfusion (NESP) could be an interesting approach to enhance the rate of ECD procurement and to reduce the risk of primary graft failure in the absence of coronary angiography in ECD. The present protocol aims to provide material details along with optimal imaging views for coronary angiography during NESP. Reproducible angiographic views were observed, including one dedicated to the right coronary artery, two for the left anterior descending artery, two for the circumflex artery, and a spider view. Continuous lactate extraction was observed in all procedures with a final median concentration of 1.10 mmol/L (0.61-1.75 mmol/L) two hours after coronary angiography, consistent with myocardial viability. The median contrast agent volume used for ex-situ imaging of the isolated perfused heart was 48 mL (38-108 mL). This protocol was reproducible for coronary artery imaging and did not impair myocardial viability during NESP.

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction.

Amyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood. Using wild-type and knocked-out MI mouse models and characterizing in vitro the exosomal communication between bone marrow-derived macrophages and activated mesenchymal stromal cells (MSC) isolated after MI, we investigated the mechanism behind Serum Amyloid A 3 (SAA3) protein overproduction in injured hearts. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived SAA3 monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from a subset of activated MSC, which, in response to MI, acquire the expression of a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN). Cardiac MSC PDPN+ communicate with and activate macrophages through their extracellular vesicles or exosomes. Specifically, MSC PDPN+ derived exosomes (MSC PDPN+ Exosomes) are enriched in SAA3 and exosomal SAA3 protein engages with Toll-like receptor 2 (TRL2) on macrophages, triggering an overproduction and impaired clearance of SAA3 proteins, resulting in aggregation of SAA3 monomers as rigid amyloid deposits in the extracellular space. The onset of amyloid fibers deposition alongside extra-cellular-matrix (ECM) proteins in the ischemic heart exacerbates the rigidity and stiffness of the scar, hindering the contractility of viable myocardium and overall impairing organ function. Using SAA3 and TLR2 deficient mouse models, we show that SAA3 delivered by MSC PDPN+ exosomes promotes post-MI amyloidosis. Inhibition of SAA3 aggregation via administration of a retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils, positively modulates the scar formation, and improves heart function post-MI. Overall, our findings provide mechanistic insights into post-MI amyloidosis and suggest that SAA3 may be an attractive target for effective scar reversal after ischemic injury and a potential target in multiple diseases characterized by a similar pattern of inflammation and amyloid deposition. What is known? Accumulation of rigid amyloid structures in the left ventricular wall impairs ventricle contractility.After myocardial infarction cardiac Mesenchymal Stromal Cells (MSC) acquire Podoplanin (PDPN) to better interact with immune cells.Amyloid structures can accumulate in the heart after chronic inflammatory conditions. What information does this article contribute? Whether accumulation of cumbersome amyloid structures in the ischemic scar impairs left ventricle contractility, and scar reversal after myocardial infarction (MI) has never been investigated.The pathophysiological relevance of PDPN acquirement by MSC and the functional role of their secreted exosomes in the context of post-MI cardiac remodeling has not been investigated.Amyloid structures are present in the scar after ischemia and are composed of macrophage-derived Serum Amyloid A (SAA) 3 monomers, although mechanisms of SAA3 overproduction is not established. Here, we report that amyloidosis, a secondary phenomenon of an already preexisting and prolonged chronic inflammatory condition, occurs after MI and that amyloid structures are composed of macrophage-derived SAA3 monomers. Frequently studied cardiac amyloidosis are caused by aggregation of immunoglobulin light chains, transthyretin, fibrinogen, and apolipoprotein in a healthy heart as a consequence of systemic chronic inflammation leading to congestive heart failure with various types of arrhythmias and tissue stiffness. Although chronic MI is considered a systemic inflammatory condition, studies regarding the possible accumulation of amyloidogenic proteins after MI and the mechanisms involved in that process are yet to be reported. Here, we show that SAA3 overproduction in macrophages is triggered in a Toll-like Receptor 2 (TLR2)-p38MAP Kinase-dependent manner by exosomal communication from a subset of activated MSC, which, in response to MI, express a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin. We provide the full mechanism of this phenomenon in murine models and confirm SAA3 amyloidosis in failing human heart samples. Moreover, we developed a retro-inverso D-peptide therapeutic approach, "DRI-R5S," specifically designed to bind SAA3 monomers and prevent post-MI aggregation and deposition of SAA3 amyloid fibrils without interfering with the innate immune response.

Assessment of Myocardial Viability in Ischemic Cardiomyopathy With Reduced Left Ventricular Function Undergoing Coronary Artery Bypass Grafting.

We aim to provide a comprehensive review of the current state of knowledge of myocardial viability assessment in patients undergoing coronary artery bypass grafting (CABG), with a focus on the clinical markers of viability for each imaging modality. We also compare mortality between patients with viable myocardium and those without viability who undergo CABG. A systematic database search with meta-analysis was conducted of comparative original articles (both observations and randomized controlled studies) of patients undergoing CABG with either viable or nonviable myocardium, in EMBASE, MEDLINE, Cochrane database, and Google Scholar, from inception to 2022. Imaging modalities included were dobutamine stress echocardiography (DSE), cardiac magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). A total of 17 studies incorporating a total of 2317 patients were included. Across all imaging modalities, the relative risk of death post-CABG was reduced in patients with versus without viability (random-effects model: odds ratio: 0.42; 95% confidence interval: 0.29-0.61; p < 0.001). Imaging for myocardial viability has significant clinical implications as it can affect the accuracy of the diagnosis, guide treatment decisions, and predict patient outcomes. Generally, based on local availability and expertise, either SPECT or DSE should be considered as the first step in evaluating viability, while PET or CMR would provide further evaluation of transmurality, perfusion metabolism, and extent of scar tissue. The assessment of myocardial viability is an essential component of preoperative evaluation in patients with ischemic heart disease undergoing surgical revascularization. Careful patient selection and individualized assessment of viability remainparamount.

Myocardial viability: when and how to look for it, its prognostic impact and interaction with benefits of revascularization

Ischemic left ventricular dysfunction results from the combination of scar and areas of dysfunctional but viable myocardium that may improve contractile function with revascularization. The traditional paradigm states that an improvement in function after revascularization leads to improved health outcomes and that assessment of myocardial viability has a key role in predicting the benefit of revascularization and, therefore, is a prerequisite for the selection of patients to undergo this treatment option. A range of retrospective observational studies supported this "viability hypothesis". However, randomized prospective trials have not confirmed the interaction between myocardial viability and the treatment effect of revascularization, challenging the recovery of left ventricular function as the principal mechanism by which surgical revascularization improves prognosis. A conceptual shift from the traditional paradigm centered on the assessment of viability as a dichotomous variable to a more comprehensive approach founded on an alternative concept that the main goal of revascularization is to prevent further damage by protecting the residual viable myocardium from subsequent acute coronary events and ventricular arrhythmias is required.

Clinical impact of multimodality assessment of myocardial viability

AbstractCoronary artery disease (CAD) is a prevalent cause of left ventricular dysfunction. Nevertheless, effective elective revascularization, particularly surgical revascularization, can enhance long‐term outcomes and, in selected cases, global left ventricular contractility. The assessment of myocardial viability and scars is still relevant in guiding treatment decisions and selecting patients who are likely to benefit most from blood flow restoration. Although the most recent randomized studies challenge the notion of “hibernating myocardium” and the clinical usefulness of assessing myocardial viability, the advancement of imaging techniques still renders this assessment valuable in specific situations. According to the guidelines of the European Society of Cardiology, non‐invasive stress imaging may be employed to define myocardial ischemia and viability in patients with CAD and heart failure before revascularization. Currently, several non‐invasive imaging techniques are available to evaluate the presence and extent of viable myocardium. The selection of the most suitable technique should be based on the patient, clinical context, and resource availability. This narrative review evaluates the characteristics of available imaging modalities for assessing myocardial viability to determine the most appropriate therapeutic strategy.

Impact of myocardial viability assessment by NTG augmented Tc99m Sestamibi Gated SPECT on management of Coronary Artery Disease

Impact of myocardial viability assessment by NTG augmented Tc99m Sestamibi Gated SPECT on management of Coronary Artery Disease