Baseline characteristics associated with developing a clinical event or a markedly abnormal risk stratifying test were similar: rest anginal episode accompanied by ST-segment depression and occurring despite treatment with aspirin and heparin, a history of angina, older age, and family history of coronary disease. Patients with these characteristics are appropriate candidates for expeditious cardiac catheterization and consideration for revascularization, while patients without them may be suitable for medical management alone.

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Introduction Tranexamic acid (TXA) is widely used as an antifibrinolytic agent in hemorrhagic trauma patients. The beneficial effects of TXA exceed the suppression of blood loss and include the ability to decrease inflammation and edema. We found that TXA suppresses the release of mitochondrial DNA and enhances mitochondrial respiration. These results allude that TXA could operate through plasmin‐independent mechanisms. To address this hypothesis, we compared the effects of TXA on lipopolysaccharide (LPS)‐induced expression of proinflammatory cytokines in plasminogen (Plg) null and Plg heterozygous mice. Methods Plg null and Plg heterozygous mice were injected with LPS and TXA or LPS only. Four hours later, mice were sacrificed and total RNA was prepared from livers and hearts. Real time quantitative polymerase chain reaction with specific primers was used to assess the effects of LPS and TXA on the expression of pro‐inflammatory cytokines. Results LPS enhanced the expression of Tnfα in the livers and hearts of recipient mice. The co‐injection of TXA significantly decreased the effect of LPS both in Plg null and heterozygous mice. A similar trend was observed with LPS‐induced Il1α expression in hearts and livers. Conclusions The effects of TXA on the endotoxin‐stimulated expression of Tnfα and Il1α in mice do not depend on the inhibition of plasmin generation. These results indicate that TXA has other biologically important target(s) besides plasminogen/plasmin. Fully understanding the molecular mechanisms behind the extensive beneficial effects of TXA and future identification of its targets may lead to improvement in the use of TXA in trauma, cardiac, and orthopedic surgical patients.

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BACKGROUND: Decreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. OBJECTIVES: To determine the association between diastolic hydraulic forces, estimated by atrioventricular area difference (AVAD), and both diastolic function and survival. We hypothesized that decreased diastolic hydraulic forces, estimated as AVAD, would associate with survival independent of conventional diastolic dysfunction measures. METHODS: Patients (n=11,734, median [interquartile range] 3.9 [2.4-5.0] years follow-up, 1,213 events) were selected from the National Echo Database Australia based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) ≥ 50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, and no prior cardiac surgery. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. RESULTS: AVAD was weakly associated with E/e prime, left atrial volume index, and LVEF (multivariable global R2=0.15, p<0.001), and not associated with e prime and peak tricuspid regurgitation velocity. Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading (C-statistic 0.645 vs 0.607) and E/e prime (C-statistic 0.639 vs 0.621), respectively. CONCLUSIONS: Decreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and provide an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction.

BACKGROUNDBody size indexation is a foundation of the diagnostic interpretation of cardiac size measures used in imaging assessment of cardiovascular health. Body surface area (BSA) is the most commonly used metric for body size indexation of echocardiographic measures, but its use in patients who are underweight or obese is questioned (body mass index (BMI) <18·5 kg/m2 or ≥30 kg/m2, respectively). We hypothesized that mortality can be used to identify an optimal body size indexation metric for echocardiographic measures that would be a better predictor of survival than BSA regardless of BMI.METHODSIn this big data, cohort study, adult patients with no prior valve replacement were selected from the National Echo Database Australia. Survival analysis was performed for echocardiographic measures both unindexed and indexed to different body size metrics, with 5-year cardiovascular mortality as the primary endpoint.FINDINGSIndexation of echocardiographic measures (left ventricular diameter [n=337,481] and mass [n=330,959], left atrial area [n=136,989], aortic sinus diameter [n=125,130], right atrial area [n=81,699], right ventricular diameter [n=3,575], right ventricular outflow tract diameter [n=2,841]) by BSA had better prognostic performance vs unindexed measures (healthy/overweight: C-statistic 0·656 vs 0·618, average change in Akaike Information Criteria (ΔAIC) 800; underweight: C-statistic 0·669 vs 0·654, ΔAIC 15; obese: C-statistic 0·630 vs 0·612, ΔAIC 113). Indexation by other body size metrics (lean body mass or height and/or weight raised to various powers) did not improve prognostic performance versus BSA by a clinically relevant magnitude (average C-statistic increase ≤0·01), with smaller differences in higher BMI subgroups. Similar results were obtained using sex-disaggregated analysis, for indexation of other aortic or cardiac dimension or volume measures, and for all-cause mortality.INTERPRETATIONIndexing measures of cardiac and aortic size by BSA improves prognostic performance regardless of BMI, and no other body size metric has a clinically meaningful better performance.FUNDINGThis research was supported in part by grants (PI Ugander) from New South Wales Health, Heart Research Australia, and the University of Sydney.

Introduction: Decreased hydraulic force has recently been identified as a mechanism contributing to left ventricular (LV) diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). However, it is unclear if hydraulic forces are independently associated with survival. Hypothesis: Decreased diastolic hydraulic force, estimated as the atrioventricular area difference (AVAD), is associated with survival independent of conventional diastolic dysfunction measures. Methods: Patients (n=37947, median [interquartile range] 4.9 [2.9-8.0] years follow-up, 6103 events) were selected from the National Echo Database Australia based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) ≥ 50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, pericardial disease or mitral annular calcification, and no prior cardiac surgery. AVAD was calculated as the cross-sectional area difference between the LV and left atrium (LA) using circular approximation of LV end-diastolic diameter and LA end-systolic diameter. LV diastolic dysfunction grading was performed according to 2016 guidelines. Results: In multivariable linear regression, AVAD was weakly associated with E/e’, e’, peak tricuspid regurgitation velocity, and LVEF (global adjusted R2=0.11, p<0.001), but not associated with left atrial volume index (p=0.83). In multivariable Cox regression, there was an association with survival for both AVAD (chi-square 279, hazard ratio (HR) [95% confidence interval] 1.23 [1.20-1.26], p<0.001) and diastolic dysfunction grading (chi-square 1217, HR 3.21 [3.00-3.42], p<0.001). In a separate multivariable model, there was an association with survival for both AVAD (chi-square 371, HR 1.27 [1.24-1.30], p<0.001) and E/e’ (chi-square 1020, HR 1.39 [1.36-1.42], p<0.001). Conclusions: Decreased hydraulic force, estimated as AVAD, is associated with diastolic dysfunction, and provides prognostic information beyond conventional measures used to grade diastolic dysfunction. This suggests that increased LA size relative to LV size is a potential therapeutic target in HFpEF.

Methods: Protein lysates and RNA prepared from cardiac muscle from colon 26 (C26) carcinoma bearing mice at day 14 post-tumour inoculation (i.e. 15-20% total body weight loss = overt cachexia) was used in this study. Gene and protein expression studies using quantitative Real Time Polymerase Chain Reaction (qRT-PCR) and Western blotting were performed on novel candidate markers of CC in heart, which may potentially be underpinning this process.Results: There was a significant up-regulation of RNA for Similar to Mother against Decapentaplegic homolog 4 (Smad4), Gata4 and B-cell lymphoma 2 (Bcl 2 ). Concurrently, a significant increase in protein expression of Smad4, Vitamin D receptor, and phosphorylated Extracellular Signalling Kinase 1 (p-Erk1); and significant decrease in protein expression of Gata4 and p-Erk2 was found.Conclusions: Our results suggest that cardiomyopathy resulting from cancer cachexia may be due to a series of maladaptive responses where alterations in molecular pathways regulated by Smad4, Gata4 and VDR occur simultaneously. Thus, these molecular targets may be potential biomarkers, which could be targeted for diagnosis and therapy.