Effects of STAT4 on myocardial ischemia­reperfusion injury and the underlying mechanisms.

The regulation of cardiac function by the nuclear transcription factor signal transducer and activator of transcription 4 (STAT4) has been recently recognized. Nevertheless, the role and mechanisms of action of STAT4 in myocardial ischemia­reperfusion (I/R) injury remain unknown. Consequently, the present study constructed a rat model of I/R by ligation of the left anterior descending coronary artery. Following sacrifice, the rat hearts were excised and analyzed to investigated the effects of STAT4 on I/R­induced myocardial injury. Western blotting demonstrated that expression of STAT4 decreased significantly in the rat model of cardiac I/R and in H9C2 cells that were subjected to hypoxia and reoxygenation (H/R). The overexpression of STAT4 in H9C2 cells reduced cell damage and apoptosis induced by H/R. Furthermore, both in vivo and in vitro, the level of PI3K decreased significantly. Although the AKT protein expression levels were not altered, the AKT phosphorylation levels decreased significantly. STAT4 overexpression enhanced the expression of PI3K and AKT in the H9C2 cells. On the whole, the present study demonstrated that STAT4 alleviated I/R­induced myocardial injury through the PI3K/AKT signaling pathway.

Advanced myocardial characterization and function with cardiac CT.

Non-invasive imaging with characterization and quantification of the myocardium with computed tomography (CT) became feasible owing to recent technical developments in CT technology. Cardiac CT can serve as an alternative modality when cardiac magnetic resonance imaging and/or echocardiography are contraindicated, not feasible, inconclusive, or non-diagnostic. This review summarizes the current and potential future role of cardiac CT for myocardial characterization including a summary of late enhancement techniques, extracellular volume quantification, and strain analysis. In addition, this review highlights potential fields for research about myocardial characterization with CT to possibly include it in clinical routine in the future.

Stunned Myocardium as a Sequela of Acute Severe Anemia: An Adult Simulation Case for Anesthesiology Residents.

Introduction: Anesthesiologists develop anesthetic plans according to the surgical procedure, patient's medical history, and physical exams. Patients with ischemic heart disease are predisposed to intraoperative cardiac complications from surgical blood loss. Unanticipated events can lead to intraoperative complications despite careful anesthesia planning. Methods: This anesthetic management simulation was developed for the anesthesiology residency curriculum during the first clinical anesthesia year (CA 1/PGY 2 residents). A total of 23 CA 1 residents participated. A 50-minute encounter focused on a 73-year-old male who presents for an elective total hip replacement and develops acute myocardial stunning in the setting of critical acute blood loss and a delay in the transportation of blood products. Results: One hundred percent of the residents felt the simulation was educationally valuable in the immediate postsimulation survey (Kirkpatrick level 1). The follow-up survey showed that 100% of residents felt the simulation increased their knowledge of managing acute cardiac ischemia (Kirkpatrick level 2), and 93% felt it increased awareness and confidence in similar real-life situations that positively affected patient outcomes (Kirkpatrick level 3). Discussion: Our simulation provides a psychologically safe environment for anesthesiology residents to develop management skills for acute critical anemia and cardiogenic shock and foster communication skills with a surgery team.

Focal Pulsed Field Ablation for Premature Ventricular Contractions: A Multicenter Experience.

BACKGROUND: Pulsed field ablation (PFA) is a novel technology for catheter-based atrial arrhythmia treatment. Evidence of its application for ventricular arrhythmia ablation is still limited. In this study, we describe the feasibility and efficacy of focal PFA for premature ventricular contraction (PVC) ablation. METHODS: A prospective cohort of 20 patients referred for PVC ablation at 2 centers was enrolled, regardless of the presence of structural heart disease, PVC morphology, or previous ablation attempts. All procedures were performed using the CENTAURI System in combination with contact force sensing catheters and 3-dimensional electroanatomical mapping systems. Energy output and the number of applications were left to the operator's discretion. RESULTS: Eleven (55%) procedures were conducted under general anesthesia, 6 (30%) under deep sedation, and 3 (15%) under light sedation. Muscular contraction was observed in one case (5%). Median procedural and fluoroscopy times were 95.5 and 6.55 minutes, respectively. The median number of PFA applications was 8 with a median contact force of 10g. A statistically significant (76%) reduction was observed in mean peak-to-peak bipolar electrogram voltage before and after ablation (0.707 versus 0.098 mV; P=0.008). Ventricular irritative firing was observed in 11 (55%) patients after PFA. The median follow-up was 120 days. Acute procedural success was achieved in 17 of 20 (85% [95% CI, 0.70-1]) patients. Two of the patients with procedural failure had late success with >80% clinical PVC burden suppression during follow-up, and 2 of 17 patients with acute success had late PVC recurrence, which accounts for a total of 17 of 20 (85% [95% CI, 0.70-1]) patients with chronic success. Transient ST-segment depression occurred in 1 patient, and the right bundle branch block was induced in 2 others (permanently only in one case). CONCLUSIONS: PVC ablation using a focal PFA is feasible, effective, and safe, with promising acute and long-term results in several ventricular locations. Irritative firing is frequently observed. Coronary evaluation should be considered when targeting the outflow tract.

Association between hibernating myocardium and collateral circulation in patients with coronary chronic total occlusion.

Objective: To explore the association between the quantity of hibernating myocardium (HM) and collateral circulation in patients with coronary chronic total occlusion (CTO). Materials and methods: 88 CTO patients were retrospectively analyzed who underwent evaluation for HM using both 99mTc-sestamibi Single photon emission computed tomography (99mTc-MIBI SPECT) myocardial perfusion imaging (MPI) combined with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) myocardial metabolism imaging (MMI). They were divided into two groups according Rentrop grading: the poorly/well-developed collateral circulation group (PD/WD group, Rentrop grades 0-1/2-3). After adjusting for the potential confounding factors and conducting a stratified analysis, we explored the association between the HM index within CTO region and the grading of collateral circulation. Results: In the WD group, the HM index was notably higher than PD group (46.2 ± 15.7% vs. 20.9 ± 16.7%, P < 0.001). When dividing the HM index into tertiles and after adjusting for potential confounders, we observed that the proportion of patients with WD rose as the HM index increased (OR: 1.322, 95% CI: 0.893-1.750, P < 0.001), the proportion of patients with WD was 17.4%, 63.3%, and 88.6% for Tertile 1 to Tertile 3.This increasing trend was statistically significant (OR: 1.369, 95% CI: 0.873-1.864, P < 0.001), especially between Tertile 3 vs. Tertile 1 (OR: 4.330, 95% CI: 1.459-12.850, P = 0.008). Curve fitting displaying an almost linear positive correlation between the two. Conclusion: The HM index within CTO region is an independent correlation factor for the grading of coronary collateral circulation. A greater HM index corresponded to an increased likelihood of WD.

Comparison Between Histidine-Tryptophan-Ketoglutarate Cardioplegia and Cold Blood Cardioplegia for Myocardial Protection in Tetralogy of Fallot Patients Undergoing Surgical Repair: A Randomized Clinical Trial.

OBJECTIVES: This study was conducted to compare the efficacy of histidine-tryptophan-ketoglutarate (HTK) cardioplegia and cold blood cardioplegia (CBC), especially for postoperative right ventricular (RV) function after tetralogy of Fallot repair. DESIGN: Randomized, double-blinded, parallel-group, controlled clinical trial. SETTING: Ain Shams University Hospitals. PARTICIPANTS: A total of 100 children (1 to 5 years old) scheduled for tetralogy of Fallot repair. INTERVENTIONS: Patients were allocated (double-blinded 1:1 allocation ratio) to either the HTK group that received HTK cardioplegia (30 mL/kg via antegrade route) or the CBC group that received cold blood cardioplegia with blood-to-Ringer solution (4:1) in a volume of 20 mL/kg. MEASUREMENTS AND MAIN RESULTS: The HTK group showed a statistically significant reduction of the vasoactive inotropic score on admission to the pediatric intensive care unit (13.0 ± 4.1) in comparison to the CBC group (15.5 ± 5.4), with a p value of 0.011. However, after 24 hours, the vasoactive-inotropic score was comparable. Lactate level during the first 24 hours was 6.2 ± 0.7 mmol/L in the HTK group and 6.9 ± 0.4 mmol/L in the CBC group (p < 0.0001). Serial troponin measurements were lower in the HTK group (1.49 ± 0.45) compared to the CBC group (1.69 ± 0.18) at the first 72 hours postoperatively (p = 0.005). Postoperative echocardiographic assessment of RV function by means of tricuspid annular plane systolic excursion and myocardial performance index were better in the HTK group than in the CBC grpup (p < 0.05). CONCLUSIONS: HTK cardioplegia may offer better cardiac protection to pediatric patients undergoing tetralogy of Fallot repair than our institutional standard CBC with better recovery for the hypertrophic RV.

The diabetic myocardial transcriptome reveals Erbb3 and Hspa2 as a novel biomarkers of incident heart failure.

AIMS: Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers. METHODS AND RESULTS: RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with versus without DM (type 1 or 2). DEGs were validated as plasma proteins in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure and cardiovascular mortality.We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data was available for 12, with ERBB3, NRXN3 and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired left ventricular contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles. CONCLUSIONS: DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with left ventricular dysfunction, incident heart failure and cardiovascular mortality.

Automated cardiovascular MR myocardial scar quantification with unsupervised domain adaptation.

Quantification of myocardial scar from late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) images can be facilitated by automated artificial intelligence (AI)-based analysis. However, AI models are susceptible to domain shifts in which the model performance is degraded when applied to data with different characteristics than the original training data. In this study, CycleGAN models were trained to translate local hospital data to the appearance of a public LGE CMR dataset. After domain adaptation, an AI scar quantification pipeline including myocardium segmentation, scar segmentation, and computation of scar burden, previously developed on the public dataset, was evaluated on an external test set including 44 patients clinically assessed for ischemic scar. The mean ± standard deviation Dice similarity coefficients between the manual and AI-predicted segmentations in all patients were similar to those previously reported: 0.76 ± 0.05 for myocardium and 0.75 ± 0.32 for scar, 0.41 ± 0.12 for scar in scans with pathological findings. Bland-Altman analysis showed a mean bias in scar burden percentage of -0.62% with limits of agreement from -8.4% to 7.17%. These results show the feasibility of deploying AI models, trained with public data, for LGE CMR quantification on local clinical data using unsupervised CycleGAN-based domain adaptation. RELEVANCE STATEMENT: Our study demonstrated the possibility of using AI models trained from public databases to be applied to patient data acquired at a specific institution with different acquisition settings, without additional manual labor to obtain further training labels.

Global and regional cardiac magnetic resonance feature tracking left ventricular strain analysis in assessing early myocardial disease in ß thalassemia major patients.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) is the modality of choice for quantification of myocardial iron overload in ß-thalassemia major patients using the T2* sequence. CMR feature tracking (FT) is a recent magnetic resonance imaging tool that gives an idea about myocardial fibers deformation; thus, it can detect early impairment in myocardial function even before the reduction in ejection fraction. METHODS: This study aims to assess the ability of left ventricular CMR-FT in the early detection of systolic dysfunction in ß thalassemia major patients and to correlate it with the degree of myocardial iron overload measured by CMR T2*. This prospective study enrolled 57 ß thalassemia major patients who received long-term blood transfusion and 20 healthy controls. CMR was used to evaluate left ventricular volumes, ejection fraction, and the amount of myocardial T2*. A two-dimensional left ventricular FT analysis was performed. Both global and segmental left ventricular strain values were obtained. RESULTS: The mean global circumferential strain (GCS) and global radial strain (GRS) values were significantly lower in patients compared to control (P = 0.002 and P = 0.006, respectively). No correlation was found between T2* values and ejection fraction; however, there was a significant correlation between T2* values and GCS and GRS (P = 0.012 and P = 0.025, respectively) in thalassemia patients. Regional strain revealed significantly lower values of GCS and GRS in basal regions compared to apical ones (P = 0.000). CONCLUSIONS: Our study revealed that CMR-FT can play a role in the early detection of systolic impairment in thalassemia patients.

Myocardial hypertrophy: the differentiation of uremic, hypertensive, and hypertrophic cardiomyopathies by cardiac MRI.

OBJECTIVES: To apply cardiac magnetic resonance imaging (CMR) for detailed myocardial characterization in uremic cardiomyopathy (UC), hypertensive cardiomyopathy (HTN), and hypertrophic cardiomyopathy (HCM) aiming to enrich the understanding of UC's etiology and further support the development of therapeutic strategies. METHODS: A total of 152 patients (age: 49.2 ± 9.9 years; 65.8% male) underwent routine CMR from June 2016 to March 2023. Retrospectively, 53 patients with UC, 39 patients with HTN, 30 patients with HCM, and 30 healthy controls were included. Functional analysis, feature tracking of the left ventricle and left atrium, and myocardial T1, T2, and T2* mapping were performed. Statistical analysis included Pearson correlation and ROC analysis to define correlations and discriminators between groups. RESULTS: UC patients demonstrated significantly higher native T1 (p < 0.001 for all) and T2 (p < 0.002 for all) values compared with the other three groups. UC patients revealed higher left atrial reservoir strain rate (p < 0.001 for all) and left atrial conduit strain rate (p < 0.001 for all) absolute values as compared with HTN and HCM patients. A significant correlation between T1 and T2 values in UC patients (r = 0.511, p < 0.001) was found. The combination of T1 values and strain parameters was the best discriminator between UC and HTN patients (AUC = 0.872, 95% CI: 0.801-0.943) and between UC and HCM patients (AUC = 0.840, 95% CI: 0.746-0.934). CONCLUSION: UC reveals distinguishing tissue characteristics as evidenced by T1 and T2 mapping, as well as distinguishing functional strain parameters as compared with other hypertrophic phenotypes such as HTN and HCM. CRITICAL RELEVANCE STATEMENT: The use of CMR imaging in UC patients offers incremental information to elucidate its complex etiology, contributing to ongoing discourse on effective treatment pathways. KEY POINTS: This study investigated uremic, hypertensive, and hypertrophic cardiomyopathies using cardiac MRI. UC patients have higher T1 and T2 values and better preserved cardiac function. Combined strain and T1 values distinguish UC from other cardiomyopathies.

Landscape of glycolytic metabolites and their regulating proteins in myocardium from human heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) reflects half of all clinical HF yet has few therapies. Obesity and diabetes are now common comorbidities which have focused attention towards underlying myocardial metabolic defects. The profile of a major metabolic pathway, glycolytic intermediates and their regulating enzymes and ancillary pathways, remains unknown. METHODS AND RESULTS: Endomyocardial biopsies from HFpEF (n = 37) and non-failing controls (n = 21) were assayed by non-targeted or targeted metabolomics and immunoblot to determine glycolytic and ancillary pathway metabolites and protein expression of their regulating enzymes. Glucose and GLUT1 expression were higher in HFpEF, but prominent glycolytic metabolites: glucose-6-phosphate, fructose-1,6-biphosphate (F1,6bP), and 3-phosphoglycerate were reduced by -78%, -91%, and -73%, respectively, versus controls. Expression of their corresponding synthesizing enzymes hexokinase, phospho-fructokinase, and phosphoglycerate kinase were also significantly lower (all p < 0.0005). Pentose phosphate and hexosamine biosynthetic pathway metabolites were reduced while glycogen content increased. Despite proximal reduction in key glycolytic intermediates, pyruvate increased but mitochondrial pyruvate transporter (MPC1) expression was reduced. Pyruvate dehydrogenase converting pyruvate to acetyl-CoA was more activated but some Krebs cycle intermediates were reduced. This HFpEF glycolytic profile persisted after adjusting for body mass index (BMI), diabetes, age, and sex, or in subgroup analysis with controls and HFpEF matched for BMI and diabetes/insulin history. In HFpEF, BMI but not glycated haemoglobin negatively correlated with F1,6bP (p = 7e-5, r = -0.61) and phosphoenolpyruvate (p = 0.006, r = -0.46). CONCLUSIONS: Human HFpEF myocardium exhibits reduced glycolytic and ancillary pathway intermediates and expression of their synthesizing proteins. This combines features reported in HF with reduced ejection fraction and obesity/diabetes that likely exacerbate metabolic inflexibility.

The Great Mimicker: A Unique Case of Diffuse Subarachnoid Haemorrhage Simulating Acute Myocardial Infarction.

Subarachnoid haemorrhage (SAH) is a rare yet consequential medical emergency that may mimic an acute myocardial infarction (MI). SAH causes enhanced sympathetic activity, culminating in the development of neurogenic stunned myocardium (NSM), which presents as ST-segment deviations, prolonged QT intervals, T-wave inversions or Q-waves. Reperfusion therapy is contraindicated for SAH because of an increased risk of bleeding and death. Therefore, a prompt diagnosis is crucial. Here, we report a unique case of massive SAH presenting as diffuse ST-segment deviation simulating an acute MI. Our patient was brought to the emergency department after a cardiac arrest and died on day 2 of admission. LEARNING POINTS: Subarachnoid haemorrhage (SAH) can present with EKG changes and significant rise in troponin, mimicking acute coronary syndrome.SAH should be included in the differential diagnosis for patients presenting with neurological symptoms, ST-segment deviations or prolonged QT intervals.Misdiagnosis of SAH as acute coronary syndrome can lead to inappropriate use of anticoagulants or delays in necessary neurological interventions.

Prediction of Major Arrhythmic Outcomes in Ischemic Cardiomyopathy: Value of Hibernating Myocardium in PET/CT.

AIMS: Known predictors of major arrhythmic events (MAE) in patients with ischemic cardiomyopathy (ICM) include previous MAE and left ventricular ejection fraction (LVEF) ≤35%. Myocardial scars detected by perfusion imaging in ICM have been linked to MAE, but the prognostic significance of hibernating myocardium (HM) is unclear. The objective was to predict major arrhythmic events (MAE) from combined 13N-ammonia (NH3) and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in ischemic cardiomyopathy (ICM). METHODS AND RESULTS: Consecutive patients with ICM undergoing combined NH3- and FDG-PET/CT were included. HM was quantified in relation to total left ventricular myocardium (i.e. ≥7% is large). The primary outcome was MAE (sudden cardiac death, ICD therapy, sustained ventricular tachycardia/fibrillation).Among 254 patients, median baseline LVEF was 35% (IQR 28-45) and 10% had an ICD. PET/CT identified ischemia in 94 (37%), scar in 229 (90%) and HM in 195 (77%) patients. Over a median follow-up of 5.4 (IQR 2.2-9.5) years, MAE occurred in 34 patients (13%). Large HM was associated with a lower incidence of MAE (HR 0.31, 95% CI 0.1-0.8, p=0.001). After multivariate adjustment for history of MAE, LVEF ≤35% and scar ≥10%, large HM remained significantly associated with a lower incidence of MAE (p=0.016). LVEF improved over time among patients with large HM (p=0.006) but did not change in those without (p=0.610) or small HM (p=0.240). CONCLUSIONS: HM conveys a lower risk of MAE in patients with ICM. This may be explained by an increase in LVEF when a large extent of HM is present.

How well do 3D-printed tissue mimics represent the complex mechanics of biological soft tissues? An example study with Stratasys' cardiovascular TissueMatrix materials.

Tissue mimicking materials are designed to represent real tissue in applications such as medical device testing and surgical training. Thanks to progress in 3D-printing technology, tissue mimics can now be easily cast into arbitrary geometries and manufactured with adjustable material properties to mimic a wide variety of tissue types. However, it is unclear how well 3D-printable mimics represent real tissues and their mechanics. The objective of this work is to fill this knowledge gap using the Stratasys Digital Anatomy 3D-Printer as an example. To this end, we created mimics of biological tissues we previously tested in our laboratory: blood clots, myocardium, and tricuspid valve leaflets. We printed each tissue mimic to have the identical geometry to its biological counterpart and tested the samples using identical protocols. In our evaluation, we focused on the stiffness of the tissues and their fracture toughness in the case of blood clots. We found that the mechanical behavior of the tissue mimics often differed substantially from the biological tissues they aim to represent. Qualitatively, tissue mimics failed to replicate the traditional strain-stiffening behavior of soft tissues. Quantitatively, tissue mimics were stiffer than their biological counterparts, especially at small strains, in some cases by orders of magnitude. In those materials in which we tested toughness, we found that tissue mimicking materials were also much tougher than their biological counterparts. Thus, our work highlights limitations of at least one 3D-printing technology in its ability to mimic the mechanical properties of biological tissues. Therefore, care should be taken when using this technology, especially where tissue mimicking materials are expected to represent soft tissue properties quantitatively. Whether other technologies fare better remains to be seen.

N-acetylcysteine combined with insulin therapy can reduce myocardial injury induced by type 1 diabetes through the endoplasmic reticulum pathway.

With the development of Type 1 diabetes mellitus (T1DM), various complications can be caused. Hyperglycemia affects the microenvironment of cardiomyocytes, changes endoplasmic reticulum homeostasis, triggers unfolding protein response and eventually promotes myocardial apoptosis. However, insulin therapy alone cannot effectively combat the complications caused by T1DM. Forty adult beagles were randomly divided into five groups: control group, diabetes mellitus group, insulin group, insulin combined with NAC group, and NAC group. 24-hour blood glucose, 120-day blood glucose, 120-day body weight, and serum FMN content were observed, furthermore, hematoxylin-eosin staining, Periodic acid Schiff reagent staining, and Sirius red staining of the myocardium were evaluated. The protein expressions of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase 3, Bcl2, and Bax were detected. Results of the pathological section of myocardial tissue indicated that insulin combined with NAC therapy could improve myocardial pathological injury and glycogen deposition. Additionally, insulin combined with NAC therapy down-regulates the expression of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase3, and Bax. These findings suggest that NAC has a phylactic effect on myocardial injury in beagles with T1DM, and the mechanism may be related to the improvement of endoplasmic reticulum stress-induced apoptosis.

Intraindividual reproducibility of myocardial radiomic features between energy-integrating detector and photon-counting detector CT angiography.

BACKGROUND: Radiomics is not yet used in clinical practice due to concerns regarding its susceptibility to technical factors. We aimed to assess the stability and interscan and interreader reproducibility of myocardial radiomic features between energy-integrating detector computed tomography (EID-CT) and photon-counting detector CT (PCD-CT) in patients undergoing coronary CT angiography (CCTA) on both systems. METHODS: Consecutive patients undergoing clinically indicated CCTA on an EID-CT were prospectively enrolled for a PCD-CT CCTA within 30 days. Virtual monoenergetic images (VMI) at various keV levels and polychromatic images (T3D) were generated for PCD-CT, with image reconstruction parameters standardized between scans. Two readers performed myocardial segmentation and 110 radiomic features were compared intraindividually between EID-CT and PDC-CT series. The agreement of parameters was assessed using the intraclass correlation coefficient and paired t-test for the stability of the parameters. RESULTS: Eighteen patients (15 males) aged 67.6 ± 9.7 years (mean ± standard deviation) were included. Besides polychromatic PCD-CT reconstructions, 60- and 70-keV VMIs showed the highest feature stability compared to EID-CT (96%, 90%, and 92%, respectively). The interscan reproducibility of features was moderate even in the most favorable comparisons (median ICC 0.50 [interquartile range 0.20-0.60] for T3D; 0.56 [0.33-0.74] for 60 keV; 0.50 [0.36-0.62] for 70 keV). Interreader reproducibility was excellent for the PCD-CT series and good for EID-CT segmentations. CONCLUSION: Most myocardial radiomic features remain stable between EID-CT and PCD-CT. While features demonstrated moderate reproducibility between scanners, technological advances associated with PCD-CT may lead to greater reproducibility, potentially expediting future standardization efforts. RELEVANCE STATEMENT: While the use of PCD-CT may facilitate reduced interreader variability in radiomics analysis, the observed interscanner variations in comparison to EID-CT should be taken into account in future research, with efforts being made to minimize their impact in future radiomics studies. KEY POINTS: Most myocardial radiomic features resulted in being stable between EID-CT and PCD-CT on certain VMIs. The reproducibility of parameters between detector technologies was limited. PCD-CT improved interreader reproducibility of myocardial radiomic features.

Cardiac fibroblasts: answering the call.

Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network and by contributing to essential physiological processes. In response to injury such as myocardial infarction or pressure overload, fibroblasts become activated, leading to increased ECM production that can ultimately drive left ventricular remodeling and progress to heart failure. Recently, the American Journal of Physiology-Heart and Circulatory Physiology issued a call for papers on cardiac fibroblasts that yielded articles with topics spanning fibroblast physiology, technical considerations, signaling pathways, and interactions with other cell types. This mini-review summarizes those articles and places the new findings in the context of what is currently known for cardiac fibroblasts and what future directions remain.

Targeting Cyclophilin A in the Cardiac Microenvironment Preserves Heart Function and Structure in Failing Hearts.

BACKGROUND: Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function. METHODS: Employing a multidisciplinary approach encompassing in silico, in vitro, in vivo, and ex vivo experiments we studied a mouse model of cardiac hypertrophy and human heart specimen to decipher the interaction of CyPA and the cardiac microenvironment in highly relevant pre-/clinical settings. Myocardial expression of CyPA (immunohistology) and the inflammatory transcriptome (NanoString) was analyzed in human cardiac tissue derived from patients with nonischemic, noninflammatory congestive heart failure (n=187). These analyses were paralleled by a mouse model of Ang (angiotensin) II-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy), and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody. RESULTS: We observed a significant accumulation of eCyPA in both human and murine-failing hearts. Importantly, higher eCyPA expression was associated with poor clinical outcomes in patients (P=0.043) and contractile dysfunction in mice (Pearson correlation coefficient, -0.73). Further, myocardial expression of eCyPA was critically associated with an increase in myocardial hypertrophy, inflammation, fibrosis, stiffness, and cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA prevented (Ang II)-induced myocardial remodeling and dysfunction in mice. CONCLUSIONS: Our study provides strong evidence of the pathogenic role of eCyPA in remodeling, myocardial stiffening, and dysfunction in heart failure. The findings suggest that antibody-based inhibition of eCyPA may offer a novel therapeutic strategy for nonischemic heart failure. Further research is needed to evaluate the translational potential of these interventions in human patients with cardiac hypertrophy.

Puerarin-Loaded Liposomes Co-Modified by Ischemic Myocardium-Targeting Peptide and Triphenylphosphonium Cations Ameliorate Myocardial Ischemia-Reperfusion Injury.

Purpose: Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. Methods: We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. Results: In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. Conclusion: This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.