Inherent Metabolic Adaptations in Adult Spiny Mouse ( Acomys ) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction.

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse ( Acomys ) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes in Acomys compared to the non-regenerative Mus musculus . We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes' transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that Acomys cardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in Acomys at baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis in Acomys compared to Mus , underscoring the unique metabolic phenotype of Acomys hearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in Acomys . In conclusion, our study identifies unique metabolic characteristics of Acomys cardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishes Acomys as a valuable model for studying cardiac ischemic resilience in adult mammals.

Lysophosphatidic Acid-Mediated Inflammation at the Heart of Heart Failure.

PURPOSE OF REVIEW: The primary aim of this review is to provide an in-depth examination of the role bioactive lipids-namely lysophosphatidic acid (LPA) and ceramides-play in inflammation-mediated cardiac remodeling during heart failure. With the global prevalence of heart failure on the rise, it is critical to understand the underlying molecular mechanisms contributing to its pathogenesis. Traditional studies have emphasized factors such as oxidative stress and neurohormonal activation, but emerging research has shed light on bioactive lipids as central mediators in heart failure pathology. By elucidating these intricacies, this review aims to: Bridge the gap between basic research and clinical practice by highlighting clinically relevant pathways contributing to the pathogenesis and prognosis of heart failure. Provide a foundation for the development of targeted therapies that could mitigate the effects of LPA and ceramides on heart failure. Serve as a comprehensive resource for clinicians and researchers interested in the molecular biology of heart failure, aiding in better diagnostic and therapeutic decisions. RECENT FINDINGS: Recent findings have shed light on the central role of bioactive lipids, specifically lysophosphatidic acid (LPA) and ceramides, in heart failure pathology. Traditional studies have emphasized factors such as hypoxia-mediated cardiomyocyte loss and neurohormonal activation in the development of heart failure. Emerging research has elucidated the intricacies of bioactive lipid-mediated inflammation in cardiac remodeling and the development of heart failure. Studies have shown that LPA and ceramides contribute to the pathogenesis of heart failure by promoting inflammation, fibrosis, and apoptosis in cardiac cells. Additionally, recent studies have identified potential targeted therapies that could mitigate the effects of bioactive lipids on heart failure, including LPA receptor antagonists and ceramide synthase inhibitors. These recent findings provide a promising avenue for the development of targeted therapies that could improve the diagnosis and treatment of heart failure. In this review, we highlight the pivotal role of inflammation induced by bioactive lipid signaling and its influence on the pathogenesis of heart failure. By critically assessing the existing literature, we provide a comprehensive resource for clinicians and researchers interested in the molecular mechanisms of heart failure. Our review aims to bridge the gap between basic research and clinical practice by providing actionable insights and a foundation for the development of targeted therapies that could mitigate the effects of bioactive lipids on heart failure. We hope that this review will aid in better diagnostic and therapeutic decisions, further advancing our collective understanding and management of heart failure.

Prognostic Significance of Activated Monocytes in Patients with ST-Elevation Myocardial Infarction.

Circulating monocytes have different subsets, including classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++), which play different roles in cardiovascular physiology and disease progression. The predictive value of each subset for adverse clinical outcomes in patients with coronary artery disease is not fully understood. We sought to evaluate the prognostic efficacy of each monocyte subset in patients with ST-elevation myocardial infarction (STEMI). We recruited 100 patients with STEMI who underwent primary percutaneous coronary intervention (PCI). Blood samples were collected at the time of presentation to the hospital (within 6 h from onset of symptoms, baseline (BL)) and then at 3, 6, 12, and 24 h after presentation. Monocytes were defined as CD45+/HLA-DR+ and then subdivided based on the expression of CD14, CD16, CCR2, CD11b, and CD42. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, stent thrombosis, in-stent restenosis, and recurrent myocardial infarction. Univariate and multivariate Cox proportional hazards models, including baseline comorbidities, were performed. The mean age of our cohort was 58.9 years and 25% of our patients were females. Patients with high levels (above the median) of CD14+CD16++ monocytes showed an increased risk for the primary endpoint in comparison to patients with low levels; adjusted hazard ratio (aHR) for CD14+/CD16++ cells was 4.3 (95% confidence interval (95% CI) 1.2-14.8, p = 0.02), for CD14+/CD16++/CCR2+ cells was 3.82 (95% CI 1.06-13.7, p = 0.04), for CD14+/CD16++/CD42b+ cells was 3.37 (95% CI 1.07-10.6, p = 0.03), for CD14+/CD16++/CD11b+ was 5.17 (95% CI 1.4-18.0, p = 0.009), and for CD14+ HLA-DR+ was 7.5 (95% CI 2.0-28.5, p = 0.002). CD14++CD16-, CD14++CD16+, and their CD11b+, CCR2+, and CD42b+ aggregates were not significantly predictive for our composite endpoint. Our study shows that CD14+ CD16++ monocytes and their subsets expressing CCR2, CD42, and CD11b could be important predictors of clinical outcomes in patients with STEMI. Further studies with a larger sample size and different coronary artery disease phenotypes are needed to verify the findings.

C-Reactive Protein Levels and Risk of Cardiovascular Diseases: A Two-Sample Bidirectional Mendelian Randomization Study.

Elevated C-reactive protein (CRP) levels are an indicator of inflammation, a major risk factor for cardiovascular disease (CVD). However, this potential association in observational studies remains inconclusive. We performed a two-sample bidirectional Mendelian randomization (MR) study using publicly available GWAS summary statistics to evaluate the relationship between CRP and CVD. Instrumental variables (IVs) were carefully selected, and multiple approaches were used to make robust conclusions. Horizontal pleiotropy and heterogeneity were evaluated using the MR-Egger intercept and Cochran's Q-test. The strength of the IVs was determined using F-statistics. The causal effect of CRP on the risk of hypertensive heart disease (HHD) was statistically significant, but we did not observe a significant causal relationship between CRP and the risk of myocardial infarction, coronary artery disease, heart failure, or atherosclerosis. Our primary analyses, after performing outlier correction using MR-PRESSO and the Multivariable MR method, revealed that IVs that increased CRP levels also increased the HHD risk. However, after excluding outlier IVs identified using PhenoScanner, the initial MR results were altered, but the sensitivity analyses remained congruent with the results from the primary analyses. We found no evidence of reverse causation between CVD and CRP. Our findings warrant updated MR studies to confirm the role of CRP as a clinical biomarker for HHD.

Immune mechanisms of cardiac aging.

Advances in healthcare and improvements in living conditions have led to rising life expectancy worldwide. Aging is associated with excessive oxidative stress, a chronic inflammatory state, and limited tissue healing, all of which result in an increased risk of heart failure. In fact, the prevalence of heart failure approaches 40% in the ninth decade of life, with the majority of these cases suffering from heart failure with preserved ejection fraction (HFpEF). In cardiomyocytes (CMs), age-related mitochondrial dysfunction results in disrupted calcium signaling and covalent protein-linked aggregates, which cause cardiomyocyte functional disturbances, resulting in increased stiffness and diastolic dysfunction. Importantly, aging is also associated with chronic low-grade, sterile inflammation, which alters the function of interstitial cardiac cells and leads to cardiac fibrosis. Taken together, cardiac aging is associated with cellular, structural, and functional changes in the heart that contribute to the rising prevalence of heart failure in older people.

Prognostic Implication of Pre-Cannulation Cardiac Arrest in Patients Undergoing Extracorporeal Membrane Oxygenation for the Management of Cardiogenic Shock.

BACKGROUND: The application of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in contemporary management of cardiogenic shock (CS) has dramatically increased. Despite increased utilization, few predictive models exist to estimate patient survival based on pre-ECMO characteristics. Furthermore, the prognostic implications of pre-ECMO cardiac arrest are not well defined. METHODS: Utilizing an institutional VA-ECMO database, all consecutive patients undergoing VA-ECMO for the management of CS from January 1, 2014, to July 1, 2019, were identified. Survival to hospital discharge was analyzed based on cannulation indication in patients with and without pre-ECMO cardiac arrest. Patients who received extracorporeal cardiopulmonary resuscitation (eCPR) were analyzed separately. RESULTS: Of the 214 patients identified, 110 did not suffer a cardiac arrest prior to cannulation (cohort 1), 57 patients had a cardiac arrest with sustained ROSC (cohort 2), and 47 were cannulated as a component of eCPR (cohort 3). Despite sustained ROSC (cohort 2), the presence of pre-ECMO cardiac arrest was associated with a significant reduction in survival to hospital discharge (22.8% vs. 55.5% in cohort 1; p < 0.001). Comparatively, survival to discharge was similar in patients undergoing eCPR (22.8% vs. 17.0%; p = 0.464). Finally, patients with a cardiac arrest were significantly more likely to have a neurological etiology death with VA-ECMO than patients supported prior to hemodynamic collapse (18.3% vs. 2.7%; p < 0.001). This result is seen in those with sustained ROSC (21.1% vs. 2.7%; p < 0.001) and those with eCPR (14.9% vs. 2.7%; p = 0.004). CONCLUSION: In our cohort, pre-ECMO cardiac arrest carries a negative prognostic value across all indications and is associated with an increased prevalence of neurological-etiology death. This finding is true in patients with sustained ROSC as well as those resuscitated with eCPR. Cardiac arrest can inform survival probability with VA-ECMO as early implementation of VA-ECMO may mitigate adverse outcomes in patients at the highest risk of hemodynamic collapse.

Autologous CD133 + Cells and Laser Revascularization in patients with severe Ischemic Cardiomyopathy.

OBJECTIVE: We tested the hypothesis that targeted TMLR combined with intramyocardial injection of autologous CD 133+ progenitor cells is safe and feasible in patients with chronic ischemic cardiomyopathy (ICM) and no revascularization options. METHODS: Eight male patients (age 62 ± 2.4 years) with multivessel severe ischemic heart disease and no revascularization options were enrolled. Autologous CD 133 + endothelial progenitor cells were derived and purified from the bone marrow on the day of surgery using the clinical-grade closed CliniMACS system. Using a lateral thoracotomy approach, TMLR was performed, followed by transmyocardial transplantation of purified CD133 + cells (mean number of transplanted cells: 12.5 × 106) in the region surrounding the TMLR sites. These sites were selected based on ischemia on pre-procedure perfusion imaging. We performed clinical and myocardial perfusion imaging pre-procedure and then at 6- and 12-month follow-up. RESULTS: No major complications or death occurred during the procedure or during the peri-operative hospital stay. One patient died of cardiac cause 6 months post-procedure. There was a reported short-term improvement in anginal and heart failure symptoms and a modest reduction in the ischemic score as assessed by perfusion imaging. CONCLUSIONS: Our phase 1 clinical study examining the combination therapy of targeted transmyocardial laser revascularization therapy and autologous CD133 + endothelial progenitor cells in patients with chronic ICM and no revascularization options demonstrates the feasibility and short-term safety of this combined approach and warrants future larger phase 2 randomized clinical studies.

Combined Transplantation of Human MSCs and ECFCs Improves Cardiac Function and Decrease Cardiomyocyte Apoptosis After Acute Myocardial Infarction.

BACKGROUND: Ischemic heart disease, often caused by an acute myocardial infarction (AMI) is one of the leading causes of morbidity and mortality worldwide. Despite significant advances in medical and procedural therapies, millions of AMI patients progress to develop heart failure every year. METHODS: Here, we examine the combination therapy of human mesenchymal stromal cells (MSCs) and endothelial colony-forming cells (ECFCs) to reduce the early ischemic damage (MSCs) and enhance angiogenesis (ECFCs) in a pre-clinical model of acute myocardial infarction. NOD/SCID mice were subjected to AMI followed by transplantation of MSCs and ECFCs either alone or in combination. Cardiomyocyte apoptosis and cardiac functional recovery were assessed in short- and long-term follow-up studies. RESULTS: At 1 day after AMI, MSC- and ECFC-treated animals demonstrated significantly lower cardiomyocyte apoptosis compared to vehicle-treated animals. This phenomenon was associated with a significant reduction in infarct size, cardiac fibrosis, and improvement in functional cardiac recovery 4 weeks after AMI. CONCLUSIONS: The use of ECFCs, MSCs, and the combination of both cell types reduce cardiomyocyte apoptosis, scar size, and adverse cardiac remodeling, compared to vehicle, in a pre-clinical model of AMI. These results support the use of this combined cell therapy approach in future human studies during the acute phase of ischemic cardiac injury.

Tissue distribution, placental transfer and excretion of silver nanoparticles in pregnant rats after a single oral dose.

A quantitative assessment of silver nanoparticles (AgNPs) in fluids and some organs of pregnant rats as well as their fetal blood were carried out in this study. A single oral dose (1mg/kg) of AgNPs with a size range of 4-20 nm was administered to pregnant rats on the 19th of gestation. Five groups were euthanized after 10 min, 1, 6, 12, and 24 hr as well as the control group. Total Silver (Ag) contents were measured in bloods (maternal and fetal) and several organs using Inductive Coupled Plasma Optical Emission Spectroscopy (ICP-OES) followed by acid digestion. In maternal blood, AgNPs were found to increase time-dependently after 12 and 24 hr into 0.135 and 0.224 µg/ml, but it was slightly higher in fetal blood (0.32 and 0.31 µg/ml) after 10 min and 1 hr. In other samples: kidneys, liver, spleen, placenta, and uterus the data indicated that NPs were rapidly absorbed from the dosing site (gastrointestinal tract) as evidenced by the detection of Ag in the analyzed samples (fluids and tissues). On the other hand, the cumulative percentages of excretion level in urine was 8.25% which was higher than in feces (4.77%) after 24 hr. These findings indicate the ability of AgNPs to accumulate in pregnant rats and transfer to their fetus imposing adverse outcomes and male formation. Thus, further investigations must be followed for direct and/or indirect exposure to such NPs before decision for their practices.

Gelatin coating enhances therapeutic cell adhesion to the infarcted myocardium via ECM binding.

Acute myocardial infarction (AMI) results in weakening of the heart muscle and an increased risk for chronic heart failure. Therapeutic stem cells have been shown to reduce inflammatory signaling and scar tissue expansion, despite most of these studies being limited by poor retention of cells. Gelatin methacrylate (GelMA) coatings have been shown to increase the retention of these therapeutic cells near the infarct. In this work, we evaluate two different potential binding partners for GelMA-coated bone marrow cells (BMCs) and myocardial tissue: the extracellular matrix (ECM) and interstitial non-cardiomyocytes. While cells containing ß1 integrins mediate cell-ECM adhesion in vivo, these cells do not promote binding to our collagen-degraded, GelMA coating. Specifically, microscopic imagining shows that even with high integrin expression, GelMA-coated BMCs do not bind to cells within the myocardium. Alternatively, BMC incubation with decellularized heart tissue results in higher adhesion of coated cells versus uncoated cells supporting our GelMA-ECM binding mode. To further evaluate the ECM binding mode, cells were incubated on slides modified with one of three different major heart ECM components: collagen, laminin, or fibronectin. While all three components promoted higher adhesion than unmodified glass, collagen-coated slides resulted in a significantly higher adhesion of GelMA-coated BMCs over laminin and fibronectin. Incubation with unmodified BMCs confirmed that without a GelMA coating minimal adhesion of BMCs occurred. We conclude that GelMA cellular coatings significantly increase the binding of cells to collagen within the ECM. Our results provide progress towards a biocompatible and easily translatable method to enhance the retention of transplanted cells in human studies.

Characteristics, Process Metrics, and Outcomes Among Patients With ST-Elevation Myocardial Infarction in Rural vs Urban Areas in the US: A Report From the US National Cardiovascular Data Registry.

Importance: Patients with ST-segment elevation myocardial infarction (STEMI) living in rural settings often have worse clinical outcomes compared with their urban counterparts. Whether this discrepancy is due to clinical characteristics or delays in timely reperfusion with primary percutaneous coronary intervention (PPCI) or fibrinolysis is unclear. Objective: To assess process metrics and outcomes among patients with STEMI in rural and urban settings across the US. Design, Setting, and Participants: This cross-sectional multicenter study analyzed data for 70 424 adult patients with STEMI from the National Cardiovascular Data Registry Chest Pain-MI Registry in 686 participating US hospitals between January 1, 2019, and June 30, 2020. Patients without a valid zip code were excluded, and those transferred to a different hospital during the course of the study were excluded from outcome analysis. Main Outcomes and Measures: In-hospital mortality and time-to-reperfusion metrics. Results: This study included 70 424 patients with STEMI (median [IQR] age, 63 [54-73] years; 49 850 [70.8%] male and 20 574 [29.2%] female; patient self-reported race: 6753 [9.6%] Black, 60 114 [85.4%] White, and 2096 [3.0%] of another race [including American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander]; 5281 [7.5%] individuals of Hispanic or Latino ethnicity) in 686 hospitals (50 702 [72.0%] living in urban zip codes and 19 722 [28.0%] in rural zip codes). Patients from rural settings were less likely to undergo PPCI compared with patients from urban settings (14 443 [73.2%] vs 43 142 [85.1%], respectively; P < .001) and more often received fibrinolytics (2848 [19.7%] vs 937 [2.7%]; P < .001). Compared with patients from urban settings, those in rural settings undergoing PPCI had longer median (IQR) time from first medical contact to catheterization laboratory activation (30 [12-42] minutes vs 22 [15-59] minutes; P < .001) and longer median (IQR) time from first medical contact to device (99 minutes [75-131] vs 81 [66-103] minutes; P < .001), including those who arrived directly at PPCI centers (83 [66-107] minutes vs 78 [64-97] minutes; P < .001) and those who transferred to PPCI centers from another treatment center (125 [102-163] minutes vs 103 [85-135] minutes; P < .001). Among those who transferred in, median (IQR) door-in-door-out time was longer in patients from rural settings (63 [41-100] minutes vs 50 [35-80] minutes; P < .001). Out-of-hospital cardiac arrest was more common in patients from urban vs rural settings (3099 [6.1%] vs 958 [4.9%]; P < .001), and patients from urban settings were more likely to present with heart failure (4112 [8.1%] vs 1314 [6.7%]; P < .001). After multivariable adjustment, there was no significant difference in in-hospital mortality between rural and urban groups (adjusted odds ratio, 0.97; 95% CI, 0.89-1.06). Conclusions and Relevance: In this large cohort of patients with STEMI from US hospitals participating in the National Cardiovascular Data Registry Chest Pain-MI Registry, patients living in rural settings had longer times to reperfusion, were less likely to receive PPCI or meet guideline-recommended time to reperfusion, and more frequently received fibrinolytics than patients living in urban settings. However, there was no difference in adjusted in-hospital mortality between patients with STEMI from urban and rural settings.

Trends and Outcomes of Oral Anticoagulation With Direct Current Cardioversion for Atrial Fibrillation/Flutter at an Academic Medical Center.

Background: Increasing reports suggest the safe use of direct oral anticoagulants (DOACs) in electrical cardioversion. The aim of this study was to assess the trends and 30-day outcomes associated with anticoagulation for cardioversion. Methods: Patients who underwent electrical cardioversion from January 2015 to October 2020 with a 30-day follow-up were included; and outcomes including stroke, transient ischemic attack, intracranial hemorrhage (ICH), and major gastrointestinal bleeding were recorded. Results: Of the 515 patients, 351 (68%) were men and 164 (32%) were women, with a mean CHA2DS2VASc score of 2.6 ± 1.6. Outpatient apixaban use increased from 10% in 2015 to 46% in 2020 (P < 0.001) with a decline in the use of warfarin from 24% in 2015 to 10% in 2020 (P = 0.023). Apixaban use peri-procedurally for cardioversion increased from 32% in 2015 to 35% in 2020 (P = 0.317), while warfarin use decreased from 23% in 2015 to 14% in 2020 (P = 0.164). At discharge, apixaban prescriptions increased from 21% in 2015 to 61% in 2020 (P < 0.001), while warfarin prescriptions declined from 30% in 2015 to 13% in 2020 (P = 0.009). No ICH was recorded in the 30 days after cardioversion. Ischemic stroke occurred in four (0.7%) patients with one (0.29%) of the 338 patients on a DOAC, one (0.8%) of the 124 patients on warfarin and two (5.5%) of the 36 patients not receiving anticoagulation post cardioversion. There were seven (1%) major gastrointestinal bleeding events in patients on oral anticoagulation, of which four (3%) were on warfarin and three (0.8%) were on DOACs. Conclusions: Our study shows the increasing and safe use of DOACs for the purpose of cardioversion. The rates of 30-day ischemic stroke post cardioversion were low and only occurred in patients admitted in the intensive care unit.

Predicting mortality in nonsurgical patients before cannulation for veno-arterial extracorporeal life support: Development and validation of the LACT-8 score.

OBJECTIVES: We sought to derive and validate a model to predict inpatient mortality after veno-arterial extracorporeal life support (VA-ECLS) based on readily available, precannulation clinical data. BACKGROUND: Refractory cardiogenic shock supported by VA-ECLS is associated with high morbidity and mortality. METHODS: VA-ECLS cases at our institution from January 2014 through July 2019 were retrospectively reviewed. Exclusion criteria were cannulation: (1) at another institution; (2) for primary surgical indication; or (3) for extracorporeal cardiopulmonary resuscitation. Multivariable logistic regression compared those with and without inpatient mortality. Multiple imputation was performed and optimism-adjusted area under the curve (oAUC) values were computed. RESULTS: VA-ECLS cases from August 2019 through November 2020 were identified as a validation cohort. In the derivation cohort (n = 135), the final model included Lactate (mmol/L), hemoglobin (g/dl; Anemia), Coma (Glasgow Coma Scale [GCS] < 8) and resusciTATEd cardiac arrest (LACTATE score; oAUC = 0.760). In the validation cohort (n = 30, LACTATE showed similar predictability [AUC = 0.710]). A simplified (LACT-8) score was derived by dichotomizing lactate (>8) and hemoglobin (<8) and summing together the number of components for each patient. LACT-8 performed similarly (derivation, oAUC = 0.724; validation, AUC = 0.725). In the derivation cohort, both scores outperformed SAVE (oAUC = 0.568) and SOFA (oAUC = 0.699) scores. A LACT-8 ≥ 3 had a specificity for mortality of 97.9% and 92.9%, in the derivation and validation cohorts, respectively. CONCLUSIONS: The LACT-8 score can predict inpatient mortality prior to before cannulation for VA-ECLS. LACT-8 can be implemented utilizing clinical data without the need for an online calculator.

Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

BACKGROUND: Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis. METHODS: We queried Veterans Affairs' databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes. RESULTS: Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67-6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79-0.83], P<0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70-0.74], P<0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes. CONCLUSIONS: In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.

Adult spiny mice (Acomys) exhibit endogenous cardiac recovery in response to myocardial infarction.

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). While Acomys species exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baseline Acomys cardiac anatomy and function in comparison with commonly used inbred and outbred laboratory Mus strains (C57BL6 and CFW). While our results demonstrated comparable cardiac anatomy and function between Acomys and Mus, Acomys exhibited a higher percentage of cardiomyocytes displaying distinct characteristics. In response to myocardial infarction, all animals experienced a comparable level of initial cardiac damage. However, Acomys demonstrated superior ischemic tolerance and cytoprotection in response to injury as evidenced by cardiac functional stabilization, higher survival rate, and smaller scar size 50 days after injury compared to the inbred and outbred mouse strains. This phenomenon correlated with enhanced endothelial cell proliferation, increased angiogenesis, and medium vessel maturation in the peri-infarct and infarct regions. Overall, these findings demonstrate augmented myocardial preservation in spiny mice post-MI and establish Acomys as a new adult mammalian model for cardiac research.

Regional end-systolic circumferential strain demonstrates compensatory segmental contractile function in patients with ST-segment elevation myocardial infarction.

Myocardial strain has shown tremendous promise as a potential diagnostic tool for characterizing ventricular function. With regards to myocardial infarction, global circumferential strain (CS) can be used to assess overall function, while regional CS can identify local alterations in contractility. Currently, there is a lack of data related to regional strain in patients with ST-segment elevation myocardial infarction (STEMI). Thus, the goal of this study was to quantify regional strain patterns in STEMI and normal control patients, measuring both peak CS and end-systolic (ES) CS in the mid-ventricular region. This was done by conducting cardiac magnetic resonance (CMR) imaging acutely after STEMI patients underwent primary percutaneous coronary intervention. The CMR datasets were then analyzed using feature-tracking of the cine images. The patients were broken into three groups: (1) control patients (N = 18), (2) STEMI patients with ejection fraction (EF) ≥ 50% (N = 20), and (3) STEMI patients with EF < 50% (N = 20). The key result of the analysis was that ES CS detected a significant increase in the magnitude of strain in the non-infarcted tissue of STEMI patients with EF ≥ 50% when compared to STEMI patients with EF < 50%, whereas peak CS did not detect any differences. This implies that the tissue in this region is contracting more strongly compared to non-infarcted tissue in STEMI patients with EF < 50%. Thus, regional ES CS could potentially be utilized as a diagnostic tool for assessing STEMI patients, by detecting regional changes in contractility after PCI, which could assist in treatment planning.

Sex Differences in Trends and In-Hospital Outcomes Among Patients With Critical Limb Ischemia: A Nationwide Analysis.

Background Critical limb ischemia (CLI) represents the most severe form of peripheral artery disease and is associated with significant mortality and morbidity. Contemporary data comparing the sex differences in trends, revascularization strategies, and in-hospital outcomes among patients with CLI are scarce. Methods and Results Using the National Inpatient Sample database years 2002 to 2015, we identified hospitalizations for CLI. Temporal trends for hospitalizations for CLI were evaluated. The differences in demographics, revascularization, and in-hospital outcomes between both sexes were compared. Among 2 400 778 CLI hospitalizations, 43.6% were women. Women were older and had a higher prevalence of obesity, hypertension, heart failure, and prior stroke. Women were also less likely to receive any revascularization (34.7% versus 35.4%, P<0.001), but the trends of revascularization have been increasing among both sexes. Revascularization was associated with lower in-hospital mortality among women (adjusted odds ratio [OR], 0.76; 95% CI, 0.71-0.81) and men (adjusted OR, 0.69; 95% CI, 0.65-0.73). On multivariable analysis adjusting for patient- and hospital-related characteristics as well as revascularization, women had a higher incidence of in-hospital mortality, postoperative hemorrhage, need for blood transfusion, postoperative infection, ischemic stroke, and discharge to facilities compared with men. Conclusions In this nationwide contemporary analysis of CLI hospitalizations, women were older and less likely to undergo revascularization. Women had a higher incidence of in-hospital mortality and bleeding complications compared with men. Sex-specific studies and interventions are needed to minimize these gaps among this high-risk population.