Post-myocardial Infarction Mortality Research Articles

Examining the impact of renal dysfunction and diabetes on post-myocardial infarction mortality: insights from a comprehensive retrospective cohort study across different age groups

Aim. Chronic kidney disease (CKD) and diabetes mellitus (DM) contribute significantly to cardiovascular disease (CVD) and mortality, with prevalence increasing. The evolving demographic of myocardial infarction (MI) patients, influenced by sedentary lifestyles and advanced medical care, lacks understanding regarding the interplay of CKD, DM, age, and post-MI mortality. This study aims to address this gap by evaluating the long-term impact of CKD and DM on post-MI mortality across age groups. Methods. A retrospective cohort study utilized data from the Estonian Myocardial Infarction Registry (EMIR), Estonian Population Register (EPR), and six major hospitals in Estonia, covering AMI hospitalizations from 2012 to 2019. Statistical analyses included Cox proportional hazards regression models and Kaplan–Meier’s curves. Results. Analysis of 17,085 MI patients revealed age-dependent associations between renal function and mortality. In patients <65 years, even minor decreases in renal function increased both short-term (HR 2.79, 95% CI 1.71–4.55) and long-term (HR 1.24, 95% CI 1.05–1.47) mortality. Mortality significantly increased in patients >80 years only below an estimated glomerular filtration rate (eGFR) of 44 ml/min/1.73 m2. Newly diagnosed DM patients exhibited higher mortality rates (average HR 1.53, 95% CI 1.45–1.62), while pre-DM did not significantly differ from non-DM patients across all age groups. The DM-renal failure interaction did not significantly influence mortality. Conclusions. An age-dependent association between eGFR and post-MI outcomes emphasizes the need for personalized therapeutic approaches considering age-specific eGFR thresholds and comorbidities to optimize patient management.

Macrophage GPR18 signaling activation by Resolvin D2 mediates metabolic switch and cardiac repair after myocardial infarction.

Abstract Higher inflammatory response is a major cause of heart failure and mortality post myocardial infarction (MI), a major health problem worldwide. Resolution of inflammation, well established as an actively orchestrated programmed response, is mediated by specialized pro-resolving lipid mediators (SPM) and cellular processes like efferocytosis. Resolvin D2 (RvD2), one such potent SPM, is expressed in leukocytes and stimulates the resolution of inflammation through signaling by its receptor GPR18. RvD2 signaling attenuates inflammation in immune-related conditions through macrophage (Mφ) cell-intrinsic and extrinsic mechanisms. The therapeutic potential of SPM has been demonstrated in treatment of sepsis and arthritis. However, the role of Mφ RvD2-GPR18 signaling in heart post-MI has not been elucidated. Here, we demonstrate (i) induction of GPR18 receptor on cardiac Mφ, (ii) &amp;gt;50% reduction in survival of myeloid- and Mφ-specific GPR18-/- mice, (iii) reduced heart function in GPR18-/- mice post-MI, (iv) a GPR18-dependent suppression of TLR4 signaling cytokines, and (v) suppression of TLR4-induced glycolytic metabolism by RvD2-GPR18 signaling in vitro in Mφ from human GPR18 chimeric adult mice. To summarize, our data suggest GPR18-dependent metabolic and phenotype switch to anti-inflammatory Mφ and cardiac repair post-MI. Further interrogation will delineate the intracellular pathways downstream of GPR18 and demonstrate the potential of RvD2 in reducing mortality post-MI.

Which indices of heart rate variability are the best predictors of mortality after acute myocardial infarction? Meta-analysis of observational studies

Cardiovascular disease is the first cause of death globally with myocardial infarction as the main event. Heart rate variability (HRV) has been associated with an increased risk of mortality post-myocardial infarction. However, which indices of heart rate variability are the best predictors for total and cardiac mortality post-myocardial infarction remains unclear. We performed a systematic review to evaluate this association. PubMed, Google Scholar, Embase and Cochrane databases were searched for studies with HRV as a predictive mortality marker. Two authors independently selected papers and extracted data and disagreements were solved with a third author. HRV indices included were SDNN, SDANN, HRV index, Total power, RMSSD, LF, HF, ULF, VLF, and LF/HF. For these clinical and statistical heterogeneity was assessed, forest and funnel plot graphs were made and sensitivity analysis, cumulative and regression meta-analysis were performed. Stata 16 was used for statistical analysis. Out of 19.960 articles found, 332 were initially selected for abstract screening and 27 finally fulfilled the criteria and allowed the extraction of data. After a sensitivity analysis, low values of SDNN, HRV index, ULF, VLF, Total Power, LF, LF/HF ratio and HF showed a statistically significant association with cardiac mortality, but SDNN index had the highest association (RR 4.19, CI95% 3.36-5.22, I2 39.7%). For total mortality, HRV index, VLF, ULF, LF, Total power, SDNNN, LF/HF ratio, HF were significantly associated, but HRV index was the index with highest association, (RR 3.60, CI95% 2.30-5.64, I2 27.5%). Based on a sensitivity analysis, the best index associated with cardiac mortality post-myocardial infarction is low values of SDNN and for total mortality is low values of HRV index.

DETERMINANTS OF MYOCARDIAL INFARCTION OUTCOMES IN A NON-PERCUTANEOUS CORONARY INTERVENTION HOSPITAL IN JAKARTA

Background: Global cardiovascular challenges persist, notably in myocardial infarction (MI). Despite studying factors such as age, sex, MI type, and comorbidities impacting survival, knowledge gaps exist, particularly in Indonesia without recent MI data, especially in non-PCI settings.&#x0D; Objectives: This study seeks to bridge the knowledge gap concerning determinants of post-MI survival in hospitals without PCI facilities in Jakarta, Indonesia.&#x0D; Methods: Adopting a retrospective cross-sectional design, 112 medical record patients from an Emergency Department of non-PCI hospital in Jakarta were selected via purposive sampling. A structured checklist was utilized to assess 16 variables and the primary endpoint was post-treatment status. The study employed Chi-square, Fisher's exact, and Likelihood ratio tests to analyze the relationship between demographics, risk Factors, and MI treatment access and the post-treatment status.&#x0D; Results: Results highlighted that of 112 myocardial infarction (MI) patients, males constituted 70.5%, with Non-ST Elevation Myocardial Infarction as the predominant subtype (57.1%). Most participants (86.6%) were ≥45 years old. Prevalence rates included hypertension (56.3%), Diabetes Mellitus (40.2%), Congestive Heart Failure (42.0%), and prior MI (27.7%). Post-MI survival stood at 92.9%, with 7.1% mortality. The results revealed a significant correlation between cardiogenic shock and MI outcomes (p=0.000), indicating a protective advantage (OR: 0.018) for those without cardiogenic shock against MI-related mortality.&#x0D; Conclusion: While cardiogenic shock has been reaffirmed as the sole predictor of post-myocardial infarction mortality in our study, it's crucial to heighten awareness of other MI determinants, including age, gender disparities, smoking status, and the dynamics of therapeutic measures. This underlines the pressing need for early identification and evidence-based management strategies.&#x0D;

Abstract GS.09: Interleukin 13 Signaling To Macrophages Promotes Recovery After Myocardial Infarction In Mice

Introduction: There is great interest in identifying signaling pathways that promote pro-reparative macrophage phenotypes in the heart. Considering the remarkable cardiac healing potential of neonatal mice, we employ this model to identify pro-reparative mechanisms that can be applied to promote cardiac repair in adults after myocardial infarction (MI). We show that IL13/IL4Rα signaling specifically on macrophages mediates neonatal heart regeneration and activation of this pathway in adult mice promotes cardiac functional recovery in post-MI. Results: We developed IL4Rα fl/fl ;CX3CR1 Cre mice (IL4Rα MacKO ) to delete IL4Rα specifically in macrophages. Neonatal IL4Rα MacKO and control mice were subjected to MI on postnatal day 1 (P1). Following injury, IL4Rα MacKO mice had significantly larger scars at 8 days post injury (dpi) and lower ejection fraction and capillary density at 21 dpi. Thus, macrophage IL4Rα expression is critical for cardiac functional recovery following injury in neonates. Using fluorescent reporter mice, we found that IL13, a ligand for IL4Rα, is produced almost exclusively by type 2 innate lymphoid cells in the neonatal heart. Interestingly, we didn’t find any cellular source of IL13 in the adult mouse heart. Considering the decline in cardiac production of IL13 from neonatal to adult stages, we postulated that reactivation of IL4Rα in the adult heart would improve cardiac healing post MI in adults. Indeed, daily IL13 administration significantly improved cardiac function post MI in adult mice, and this improvement was mediated entirely by IL4Rα expression on macrophages as IL4Rα MacKO mice showed no functional improvement with IL13 administration. Intriguingly, while IL13 administration to control mice improved cardiac function, administration to IL4Rα MacKO mice further exacerbated post MI mortality and scar size compared to animals receiving PBS, suggesting multiple cardiac cell types respond to IL13 resulting in beneficial or detrimental outcomes. Conclusions: Our data elucidates a strongly pro-reparative role for IL13 signaling directly to macrophages. While this signaling pathway is active in neonatal stages, we demonstrate that re-activation by IL13 administration is required to promote cardiac repair in adults.

Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality

Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR/GR knockout (MR/GR-KO) underwent baseline and follow-up echocardiography every 2 weeks after MI or sham operation. Behavioral testing at 4 weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of ‘depressive’ mice after MI. Serum corticosterone levels were increased but—in line with the higher vagal tone—plasma and cardiac catecholamines were decreased. MR/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit.

Effect of White Blood Cell Indices and Glycemia on Inhospital Prognosis of ST-Segment Elevated Myocardial Infarction

Background: Early risk stratification is recommended in daily clinical practice to predict adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Complete blood count and blood glucose analysis is routinely performed on admission. Hence, this study was undertaken to find out the predictive value of white blood cell (WBC) indices and glycemia to know adverse outcomes in STEMI. Methods: In an observational study conducted between December 2015 and October 2018 at a tertiary center, 400 patients with acute STEMI were included. Results: We had 400 patients of STEMI. In this study, mean total leukocyte count (TLC), total neutrophil count (TNC), neutrophil-to-lymphocyte ratio (NLR), and plasma glucose were higher in those with complications (13,449.8/mm3, 10,460.5/mm3, 5.20 and 180.8 mg%) than those without complications (11,318.3/mm3, 8581.9/mm3, 4.15, and 151.1 mg%) (P &lt; 0.05). The cutoff point of TLC &gt;13 × 1000 cells/mm3 had a sensitivity of 73.5% and specificity of 63% in predicting postmyocardial infarction mortality (area under the curve = 0.68,P&lt; 0.001). Patients with acute hyperglycemia (≥140 mg%) had higher incidence of hypotension (31.12% vs. 17.64%,P&lt; 0.05), left ventricular failure (32.14% v/s. 21.1%,P&lt; 0.05), ventricular arrhythmias (13.26% vs. 6.86%,P&lt; 0.05), and higher inhospital mortality (P = 0.0001). Multivariate analysis predicting inhospital mortality as dependent variable TLC &gt;13 × 1000 cells/mm3, TNC &gt;10.5 × 1000 cells/mms3, NLR ≥5.20, and plasma glucose &gt;140 mg/dl were the variable found to be statistically significant (P &lt; 0.05). Conclusion: The WBC indices (TLC, TNC, and NLR) and plasma glucose on admission are independent predictors of major cardiovascular events and inhospital mortality in STEMI.

Abstract 13441: Which Indices of Heart Rate Variability are the Best Predictors of Mortality After Acute Myocardial Infarction? Meta-Analysis of Observational Studies

Introduction: Cardiovascular disease is the first cause of death globally with myocardial infarction as the main event. Heart rate variability (HRV) has been associated with an increased risk of mortality post-myocardial infarction. However, which indices of heart rate variability are the best predictors for total and cardiac mortality post-myocardial infarction remains unclear. Predict mortality risk by these indices, is important as HRV is a low-cost, low-invasive, and easy biomarker to interpret. Hypothesis: Indices evaluating heart rate variability are differentially associated with cardiac and total mortality, but to date, there is no evidence about which is the best for these outcomes Methods: PubMed, Google Scholar, Embase, Cochrane databases, and grey literature were searched for studies with HRV as a predictive mortality marker. Two authors independently selected papers and extracted data. Disagreements were solved with a third author. Clinical and statistical heterogeneity was assessed. Forest and funnel plot graphs were made. HRV indices included were SDNN, SDANN, HRV index, Total power, RMSSD, pNN50, LF, HF, ULF, VLF, and LF/HF. Sensitivity analysis, cumulative and regression meta-analysis were performed. Stata 16 was used for statistical analysis. Results: From 338 articles found, 29 were included. Low values of SDNN, HRV index, HF, ULF, and VLF showed statistically significant association with cardiac mortality, but HRV index had the highest association RR: 5.10 (CI95% 3.92 - 6.65, I 2 of 22%). For overall mortality, SDNN, HRV index, LF, VLF y ULF had statistically significant association, but HRV index was the best index, RR:3.60 (CI95% 2.52- 5.15, I 2 0%). Both associations had high consistency in subgroup analysis, with quality of articles, year of publication, and different cut-off points. Conclusions: the best index associated with cardiac and total mortality post-myocardial infarction is low values of HRV index.

Intravenous ferric carboxymaltose does not provide benefits in reperfused acute myocardial infarction in the rat with normal iron status

Iron deficiency has been implicated in the pathophysiology of heart failure and myocardial ischemia and reperfusion injury. Moreover, reperfused heart seems to lose iron, thus even subjects with normal iron status could benefit from iron therapy. Impaired mitochondrial respiration and energy starvation may be among possible consequences of myocardial iron deficiency. So far no attempts have been made to treat acute coronary syndromes with iron. Thus our aim was to verify the hypothesis that intravenous iron therapy given during reperfusion of an acute myocardial infarction will reduce left ventricular remodeling and hemodynamic abnormalities in a 2-month follow-up as well as early mitochondrial dysfunction and mortality, in the rat with normal iron status. A single dose of ferric carboxymaltose was administered intravenously at 30min of reperfusion following 30min of ischemia in the rat model of myocardial infarction. Ventricular arrhythmias were monitored using a telemetric system, activity of mitochondrial enzymes was assessed using spectrophotometry, serum markers of oxidative stress and inflammation were determined and left ventricular function and remodeling were monitored using echocardiography and pressure-volume loops. Intravenous iron therapy did not affect post-myocardial infarction mortality, left ventricular size or function, ventricular arrhythmias, activity of mitochondrial respiratory chain, oxidative stress or markers of inflammation, but was not associated with any adverse effects. Although ferric carboxymaltose given at reperfusion was safe, it was ineffective in this model of reperfused myocardial infarction in the rat with normal iron status.

Can Platelet/Mean Platelet Volume ratio, Neutrophil/lymphocyte ratio, and Procalcitonin used for Predicting Prognosis in Acute Coronary Syndrome?

Objective: This study aimed to evaluate acute coronary syndrome (ACS), serum procalcitonin levels, Platelet/Mean Platelet Volume ratio (PMR) and Neutrophil/lymphocyte ratio (NLR) concerning post-myocardial infarction (MI) complications, mortality, and morbidity. Material and Method: The study included a total of 913 patients with ACS who presented to the emergency department with chest pain between January 2013 and December 2017. The patients were categorized as ST-elevated MI (STEMI), non-ST elevated MI (NSTEMI) and unstable angina (UA) according to the diagnosis. The demographic and laboratory characteristics of the patients were compared for three-vessel disease (TVD) and mortality rates. Result: Post MI complications, TVD, and mortality were significant among acute coronary syndrome groups. The three-vessel disease was mostly observed in anterior MI with a maximum rate of 58 (39.7%). Mortality was found as 23 (16.3%) in anterior MI and 18 (12.2%) in NSTEMI. Serum procalcitonin levels were highest in anterior MI. Platelet to Mean Platelet Volume ratio was higher in UA, whereas it was lower in STEMI and NSTEMI. Neutrophil to lymphocyte ratio was the lowest in UA. The cTn I values of STEMIs at 0, 6, 12 hours were higher than UA, and the 12th-hour cTnI values in anterior MI were higher than NSTEMIs. It was found that procalcitonin and NLR had a positive correlation with post-MI complications, mortality, and TVD, whereas PMR exhibited a negative correlation. Conclusion: The levels of procalcitonin, PMR, and NLR may be significant in respect of post-complications, mortality, and morbidity in acute coronary syndrome.

Lower Post Myocardial Infarction Mortality Among Women Treated at Veterans Affairs Hospitals Compared to Men

There is conflicting evidence about whether mortality after myocardial infarction is higher among women than among men. This study aimed to compare sex differences in post myocardial infarction mortality in the Veterans Affairs system, a setting where the predominant subjects are men. The Veterans Affairs Corporate Data Warehouse inpatient and laboratory chemistry databases were used to identify patients diagnosed with acute myocardial infarction from inpatient records from January 1st, 2005 to April 25th, 2015. Mortality data was obtained through the Veterans Affairs death registry. A total of 130,241 patients were identified; 127,711 men (98%) and 2,530 women (2%). Men typically had more comorbidities including congestive heart failure (54% vs. 46%, P value < 0.001), diabetes mellitus (54% vs. 48%, P value < 0.001), and chronic kidney disease (39% vs. 28%, P value < 0.001). The peak troponin-I was significantly higher among men (16.0 vs. 10.7 ng/mL, P value=0.03). The mean follow-up time was 1490.67 ± 8 days. After adjusting for differences in demographics and comorbidities, women had a significantly lower risk of mortality (hazard ration [HR]: 0.747, P value < 0.0001) as compared to men. In a health care system where the predominant subjects are men, women had better short- and long-term survival than men after an acute myocardial infarction. Further investigation is warranted to determine the reasons behind the improved outcomes in women post myocardial infarction in the veteran population.

Ultrasound-Targeted Microbubble Cavitation with Sodium Nitrite Synergistically Enhances Nitric Oxide Production and Microvascular Perfusion

Microvascular obstruction is a common repercussion of percutaneous coronary intervention for distal microembolization, ischemia-reperfusion injury and inflammation, which increases post-myocardial infarction heart failure and mortality. Ultrasound-targeted microbubble cavitation (UTMC) may resolve microvascular obstruction while activating endothelial nitric oxide synthase (eNOS) and increasing endothelium-derived nitric oxide (NO) bioavailability. Nitrite, a cardioprotective agent, offers an additional source of NO and potential synergy with UTMC. UTMC and nitrite co-therapy increased microvascular perfusion and NO concentration in a rat hindlimb model. Using N-nitro-L-arginine methyl ester for eNOS blockade, we found a three-way interaction effect between nitrite, UTMC and eNOS on microvascular perfusion and NO production. Modulating ultrasound peak negative acoustic pressure (0.33-1.5 MPa) significantly affected outcomes, while microbubble dosage (2 × 108 bubbles/mL, 1.5 mL/h to 1 × 109 bubbles/mL, 3 mL/h) did not. Nitrite co-therapy also protected against oxidative stress. Comparison of nitrite to sodium nitroprusside with UTMC revealed synergistic effects were specific to nitrite. Synergy between UTMC and nitrite holds therapeutic potential for cardiovascular disease.

P3618Underweight predicts greater risk of cardiac mortality post acute myocardial infarction

Abstract Background Increased body mass index (BMI) is a well-established risk factor for cardiovascular disease, however, patients with elevated BMI comparing to low BMI seem to have better survival, a phenomenon reported as “obesity paradox” which remains as a controversy. We investigated the effect of BMI, including underweight, normoweight, overweight and obese, on cardiac mortality post acute myocardial infarction (AMI). Methods This analysis included 3562 AMI patients with documented BMI. The baseline characteristics including clinical and laboratory parameters were collected at hospital admission for AMI. Patients were classified into 4 groups based on BMI values: underweight (BMI &lt;18.5), normoweight (BMI 18.5 to 24.9), overweight (BMI 25 to 29.9) and obese (BMI ≥30). Patients were followed up for a median of 1.9 years. The rate of cardiac death (primary endpoint) was compared among the 4 BMI groups. Cox proportional hazard models were used to adjust for potential confounders. Results Of 3562, 110 (3%) were underweight, 1579 (44%) were normoweight, 1493 (42%) were overweight, and 380 (11%) were obese. Compared to the normoweight group, subjects in overweight and obese groups were younger, more men, more hypertension, more likely to receive percutaneous coronary intervention (PCI), and had higher levels of glucose and lipids, but, lower level of N-terminal pro-brain natriuretic peptide (NTproBNP). Subjects in underweight group were older, more women, fewer diabetes, less likely to receive PCI, lower levels of glucose and lipids, but, higher level of NTproBNP and higher rates of left ventricular ejection fraction (LVEF)&lt;50%. Cardiac death over 1.9 years occurred significantly more in the underweight group (30.0%, 10.6%, 7.0% and 5.0% among the 4 groups from underweight to obese, p&lt;0.001 for trend, Figure 1). The Cox proportional hazard model revealed that underweight was an independent predictor of subsequent cardiac death (OR=2.58, 95% CI: 1.52–4.39, p&lt;0.001). Multivariate analysis identified that older age, higher levels of cardiac troponin I (cTnI) and LVEF&lt;50% were independently associated with increased risk of cardiac death. PCI significantly and independently protected AMI patients against cardiac death (OR=0.34, 95% CI: 0.23–0.49, p&lt;0.001). Conclusions Patients who were underweight were at greater risk of cardiac death post AMI. In addition, older age, higher levels of cTnI, LVEF&lt;50%, and not receiving PCI also independently predicted cardiac mortality post AMI. Acknowledgement/Funding Beijing Natural Science Foundation (No. 7194253);Scientific Research Common Program of Beijing Municipal Commission of Education (KM201910025017)

20‐HETE Antagonism Reduces Left Ventricular Remodeling Post‐Myocardial Infarction

20‐Hydroxyeicosatetraenoic acid (20‐HETE) is a cytochrome p450‐derived eicosanoid that stimulates endothelial dysfunction and inflammation via binding to its receptor, GPR75 (GPCR‐Gαq/11). Increased 20‐HETE in animals and humans is associated with hypertension, stroke, myocardial infarction (MI), metabolic syndrome (MetS), and increased reactive oxygen species (ROS). However, investigated effectiveness of 20‐HETE antagonists on ROS generation and MI size has been limited by short‐term follow up and administration of inhibitors prior to onset of MI only in healthy animals. Here, we evaluated the effect of a 20‐HETE antagonist, 20‐SOLA, administered at onset of reperfusion on post MI remodeling 48 hours and 8 weeks after reperfusion in normal (SD) and MetS (JCR:LA‐cp) rats. 20‐HETE was elevated in response to ischemia and more so during reperfusion; this elevation was greater in MetS (ischemia: 2‐fold SD and JCR; reperfusion: 3‐fold SD, 4‐fold JCR). MI size was markedly greater in JCR vs. SD rate (50% vs. 25% of LV). Treatment with 20‐SOLA significantly decreased MI size in both SD (~50%) and JCR (~65%) rats. Equivalent results were obtained in animals treated with GPR75‐shRNA‐Lnv at onset of reperfusions. 20‐SOLA improved coronary blood flow (1.00 ± 0.01 to 1.84 ± 0.03 mg/ml/g in SD to 0.99 ± 0.03 to 1.75±0.01 mg/ml/g in JCR). Mechanistically, smaller MI size in 20‐SOLA‐treated animals correlated with decreased ROS production in JCR rats (90%). Furthermore, survival and left ventricular (LV) function were preserved 8 weeks post MI in 20‐SOLA‐treated animals (ejection fraction (EF) = 80.5% (SD, 100% survival) and 82.5% (JCR, 100% survival)). This correlated with decreased ROS, preserved myocyte morphology, and preserved intact collagen. Differential activation of MMPs in SD vs. JCR rats vs. 20‐SOLA‐treated animals underlie the observed morphological, structural and functional changes. ROS production was decreased in JCR rats treated with a NOX inhibitor (~60%); NOX inhibition also markedly reduced MI size at 48h (60%) and preserved LV function at 8 weeks (EF = 74%, 85% survival) vs. non‐treated rats demonstrating an important role for NOX‐derived ROS in determining MI size and long‐term post‐MI remodeling. In the aggregate, these results indicated that targeting 20‐HETE actions may be an important consideration in prevention of detrimental LV remodeling and mortality post MI. Funding: HL093052.Support or Funding InformationFunding: HL093052This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Review of Cannabis in Chronic Kidney Disease Symptom Management.

Purpose of Review:Physical and psychological symptom burden in patients with advanced chronic kidney disease (CKD) is significantly debilitating; yet, it is often inadequately treated. Legalization of cannabis in Canada may attract increasing interest from patients for its medical use in refractory symptom management, but its indications and long-term adverse health impacts are poorly established, creating a challenge for clinicians to support its use. In this review, we summarize key clinical studies and the level of evidence for nonsynthetic cannabinoids in the treatment of common symptoms encountered in advanced stages of CKD, including chronic pain, nausea and vomiting, anorexia, pruritus, and insomnia.Sources of Information:Medline and EmbaseMethods:A search was conducted in MEDLINE and EMBASE (inception to March 1, 2018) on cannabis and CKD symptoms of interest, complemented with a manual review of bibliographies. Studies that examined synthetic cannabinoids that are manufactured to mimic the effects of ∆9-tetrahydrocannabinol such as dronabinol, levonantradol, nabilone, and ajulemic acid were excluded. We focused on studies with higher level of evidence where available, and quality of studies was graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence (1a to 5).Findings:Based on studies conducted in patients without renal impairment, those treated with nonsynthetic cannabinoids were 43% to 300% more likely to report a ≥30% reduction in chronic neuropathic pain compared with placebo. However, there is currently insufficient evidence to recommend nonsynthetic cannabinoids for other medical indications, although preliminary investigation into topical endocannabinoids for uremia-induced pruritus in end-stage renal disease is promising. Finally, any benefits of cannabis may be offset by potential harms in the form of cognitive impairment, increased risk of mortality post-myocardial infarction, orthostatic hypotension, respiratory irritation, and malignancies (with smoked cannabis).Limitations:Nonsynthetic cannabinoid preparations were highly variable between studies, sample sizes were small, and study durations were short. Due to an absence of studies conducted in CKD, recommendations were primarily extrapolated from the general population.Implications:Until further studies are conducted, the role of nonsynthetic cannabinoids for symptom management in patients with CKD should be limited to the treatment of chronic neuropathic pain. Clinicians need to be cognizant that nonsynthetic cannabinoid preparations, particularly smoked cannabis, can pose significant health risks and these must be cautiously weighed against the limited substantiated therapeutic benefits of cannabis in patients with CKD.

Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality.

Macrophage phagocytosis of dead cells is a prerequisite for inflammation resolution. Because CXCL4 induces macrophage phagocytosis in vitro, we examined the impact of exogenous CXCL4 infusion on cardiac wound healing and macrophage phagocytosis following myocardial infarction (MI). CXCL4 expression significantly increased in the infarct region beginning at Day 3 post-MI, and macrophages were the predominant source. Adult male C57BL/6J mice were subjected to coronary artery occlusion, and MI mice were randomly infused with recombinant mouse CXCL4 or saline beginning at 24 h post-MI by mini-pump infusion. Compared with saline controls, CXCL4 infusion dramatically reduced 7 day post-MI survival [10% (3/30) for CXCL4 vs. 47% (7/15) for saline, P < 0.05] as a result of acute congestive heart failure. By echocardiography, CXCL4 significantly increased left ventricular (LV) volumes and dimensions at Day 5 post-MI (all P < 0.05), despite similar infarct areas compared with saline controls. While macrophage numbers were similar at Day 5 post-MI, CXCL4 infusion increased Ccr4 and Itgb4 and decreased Adamts8 gene levels in the infarct region, all of which linked to CXCL4-mediated cardiac dilation. Isolated Day 5 post-MI macrophages exhibited comparable levels of M1 and M4 markers between saline and CXCL4 groups. Interestingly, by both ex vivo and in vitro phagocytosis assays, CXCL4 reduced macrophage phagocytic capacity, which was connected to decreased levels of the phagocytosis receptor CD36. In vitro, a CD36 neutralizing antibody (CD36Ab) significantly inhibited macrophage phagocytic capacity. The combination of CXCL4 and CD36Ab did not have an additive effect, indicating that CXCL4 regulated phagocytosis through CD36 signalling. CXCL4 infusion significantly elevated infarct matrix metalloproteinase (MMP)-9 levels at Day 5 post-MI, and MMP-9 can cleave CD36 as a down-regulation mechanism. CXCL4 infusion impaired macrophage phagocytic capacity by reducing CD36 levels through MMP-9 dependent and independent signalling, leading to higher mortality and LV dilation.

Cellular and molecular approaches to enhance myocardial recovery after myocardial infarction.

Reperfusion therapy has resulted in significant improvement in post-myocardial infarction morbidity and mortality in over the last 4 decades. Nonetheless, it is well recognized that simply restoring patency of the epicardial artery may not stop or reverse damage at microvascular level, and myocardial salvage is often suboptimal. Numerous efforts have been undertaken to elucidate the mechanisms underlying extensive myonecrosis to facilitate the discovery of therapies to provide additional and incremental benefits over current therapeutic pathways. To date, conclusively effective strategies to promote myocardial recovery have not yet been established. Novel approaches are investigating the foundational cellular and molecular bases of myocardial ischemia and irreversible injury. Herein, we review the emerging concepts and proposed therapies that may improve myocardial protection and reduce infarct size. We examine the preclinical and clinical evidence for reduced infarct size with these strategies, including anti-inflammatory agents, intracellular ion channel modulators, agents affecting the reperfusion injury salvage kinase (RISK) and nitric oxide signaling pathways, modulators of mitochondrial function, anti-apoptotic agents, and stem cell and gene therapy. We review the potential reasons of failures to date and the potential for new strategies to further promote myocardial recovery and improve prognosis.

Graphic report of the results from propensity score method analyses

To increase transparency in studies reporting propensity scores by using graphical methods that clearly illustrate (1) the number of participant exclusions that occur as a consequence of the analytic strategy and (2) whether treatment effects are constant or heterogeneous across propensity scores. We applied graphical methods to a real-world pharmacoepidemiologic study that evaluated the effect of initiating statin medication on the 1-year all-cause mortality post-myocardial infarction. We propose graphical methods to show the consequences of trimming and matching on the exclusion of participants from the analysis. We also propose the use of meta-analytical forest plots to show the magnitude of effect heterogeneity. A density plot with vertical lines demonstrated the proportion of subjects excluded because of trimming. A frequency plot with horizontal lines demonstrated the proportion of subjects excluded because of matching. An augmented forest plot illustrates the amount of effect heterogeneity present in the data. Our proposed techniques present additional and useful information that helps readers understand the sample that is analyzed with propensity score methods and whether effect heterogeneity is present.

Abstract P349: Kidney Function Modifies the Positive Association of Troponin With 30 Day Mortality After Myocardial Infarction

Introduction: Increased levels of cardiac troponin at the time of myocardial infarction (MI) have been shown to predict mortality. However, troponin is renally cleared and kidney function itself impacts mortality. We tested the hypothesis that baseline kidney function modifies the relationship between peak cardiac troponin I ratio (cTnI-R) and 30 day mortality after MI. Methods: Data from the Veterans Health Administration was used to create a national sample of hospitalized Veterans with a discharge diagnosis of MI between 2002 and 2015. The peak cTnI-R, calculated as the highest cTnI during the hospitalization compared to the upper limit of normal for each assay, was used as a proxy for the date of the MI event. Veterans with a history of cancer or blood vessel surgery 5 days before peak cTnI were excluded. The closest estimated glomerular filtration rate (eGFR) measured within 2 years prior to hospital admission was used as a marker of baseline kidney function. We created quartiles of peak cTnI-R and clinically relevant levels of eGFR (&lt;30, 30-44, 45-59, and 60+ ml/min/1.73 m 2 ) and fitted Cox regression adjusting for calendar year, age, length of hospital stay, region, diabetes, major mental health conditions and baseline use of diuretics, anti-hypertensives and anti-lipemics. We used subjects in the first quartile of troponin with eGFR of 60+ as common reference. Results: Among 56,073 Veterans hospitalized for MI, mean age was 67 and 98% were men. During 28 days mean follow up, 4,533 deaths occurred. 30 day mortality steadily increased across quartiles of peak cTnI-R; however, the increase in mortality was higher in eGFR below 30, suggesting effect modification of troponin-mortality relation by eGFR (p for interaction between eGFR and troponin 0.03) (Figure). Conclusions: Our data show that the positive relation of troponin with 30 day mortality post MI is modified by kidney function. Veterans with impaired kidney function carry a higher risk of 30 day mortality after MI compared to those with normal eGFR for a given troponin quartile.

Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis

ObjectivesPatients with rheumatoid arthritis (RA) are at increased risk of myocardial infarction (MI) compared with subjects without RA, with the increased risk driven potentially by inflammation. Tumour necrosis factor inhibitors...