Vascular effects of serelaxin in patients with stable coronary artery disease:A randomized placebo-controlled trial

Aims: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). Methods and results: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. Conclusion: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion

Implementation of more sensitive cardiac troponin T assay in a state-wide health service

Aims: Explore the impact of deploying high-sensitivity (hs) cardiac troponin T (cTnT) assay across a state-wide health service. Methods and results: Presentations to emergency departments of six tertiary hospitals between January 2008 and August 2019 were included; standard cTnT assay was superseded by hs-cTnT in June 2011 without changing the reference range (≥30 ng/L reported as elevated), despite cTnT level of 30 ng/L being equivalent to ∼44 ng/L with hs-cTnT. Clinical outcomes were captured using state-wide linked health records. Interrupted time series analyses were used adjusted for seasonality and multiple co-morbidities using propensity score matching allowing for correlation within hospitals. In total, 614,847 presentations had ≥1 troponin measurement. Clinical ordering of troponin decreased throughout the study with no increase in elevated measurements amongst those tested with hs-cTnT. Small but statistically significant changes in index myocardial infarction (MI) diagnosis (−0.36%/year, 95%CI [confidence interval]:–0.48, −0.24,p < 0.001) and invasive coronary angiography (0.12%/year,95%CI:0, 0.24,p = 0.02) were seen, with no impact on death/MI at 30 days or 3-year survival in episodes of care (EOCs) with elevated cTnT after hs-cTnT implementation. Length of stay (LOS) was shorter among those with an elevated hs-cTnT (−4.44 h/year, 95%CI:–5.27, −3.60, p < 0.001). Non-elevated cTnT EOCs demonstrated shorter total LOS and improved 3-year survival (adjusted hazard ratio:0.90, 95%CI:0.83, 0.97,p = 0.008) although death/MI at 30 days was unchanged using hs-cTnT. Conclusion: Widespread implementation of hs-cTnT without altering clinical thresholds reported to clinicians provided significantly shorter LOS without a clinically significant impact on clinical outcomes. A safer cohort with non-elevated cTnT was identified by hs-cTnT compared to the standard cTnT assay.</p

Comparison of Random Forest and Kriging Models for Soil Organic Carbon Mapping in the Himalayan Region of Kashmir

The knowledge about the spatial distribution of soil organic carbon stock (SOCS) helps in sustainable land-use management and ecosystem functioning. No such study has been attempted in the complex topography and land use of Himalayas, which is associated with great spatial heterogeneity and uncertainties. Therefore, in this study digital soil mapping (DSM) was used to predict and evaluate the spatial distribution of SOCS using advanced geostatistical methods and a machine learning algorithm in the Himalayan region of Jammu and Kashmir, India. Eighty-three soil samples were collected across different land uses. Auxiliary variables (spectral indices and topographic parameters) derived from satellite data were used as predictors. Geostatistical methods—ordinary kriging (OK) and regression kriging (RK)—and a machine learning method—random forest (RF)—were used for assessing the spatial distribution and variability of SOCS with inter-comparison of models for their prediction performance. The best fit model validation criteria used were coefficient of determination (R2) and root mean square error (RMSE) with resulting maps validated by cross-validation. The SOCS concentration varied from 1.12 Mg/ha to 70.60 Mg/ha. The semivariogram analysis of OK and RK indicated moderate spatial dependence. RF (RMSE = 8.21) performed better than OK (RMSE = 15.60) and RK (RMSE = 17.73) while OK performed better than RK. Therefore, it may be concluded that RF provides better estimation and spatial variability of SOCS; however, further selection and choice of auxiliary variables and higher soil sampling density could improve the accuracy of RK prediction

Comparison of semi-automated methods to quantify infarct size and area at risk by cardiovascular magnetic resonance imaging at 1.5T and 3.0T field strengths.

Background: There is currently no gold standard technique for quantifying infarct size (IS) and ischaemic area-at-risk (AAR [oedema]) on late gadolinium enhancement imaging (LGE) and T2-weighted short tau inversion recovery imaging (T2w-STIR) respectively. This study aimed to compare the accuracy and reproducibility of IS and AAR quantification on LGE and T2w-STIR imaging using Otsu’s Automated Technique (OAT) with currently used methods at 1.5T and 3.0T post acute ST-segment elevation myocardial infarction (STEMI). Methods: Ten patients were assessed at 1.5T and 10 at 3.0T. IS was assessed on LGE using 5–8 standard-deviation thresholding (5-8SD), full-width half-maximum (FWHM) quantification and OAT. AAR was assessed on T2w-STIR using 2SD and OAT. Accuracy was assessed by comparison with manual quantification. Interobserver and intraobserver variabilities were assessed using Intraclass Correlation Coefficients and Bland-Altman analysis. IS using each technique was correlated with left ventricular ejection fraction (LVEF). Results: FWHM and 8SD-derived IS closely correlated with manual assessment at both field strengths (1.5T: 18.3 ± 10.7% LV Mass [LVM] with FWHM, 17.7 ± 14.4% LVM with 8SD, 16.5 ± 10.3% LVM with manual quantification; 3.0T: 10.8 ± 8.2% LVM with FWHM, 11.4 ± 9.0% LVM with 8SD, 11.5 ± 9.0% LVM with manual quantification). 5SD and OAT overestimated IS at both field strengths. OAT, 2SD and manually quantified AAR closely correlated at 1.5T, but OAT overestimated AAR compared with manual assessment at 3.0T. IS and AAR derived by FWHM and OAT respectively had better reproducibility compared with manual and SD-based quantification. FWHM IS correlated strongest with LVEF. Conclusions: FWHM quantification of IS is accurate, reproducible and correlates strongly with LVEF, whereas 5SD and OAT overestimate IS. OAT accurately assesses AAR at 1.5T and with excellent reproducibility. OAT overestimated AAR at 3.0T and thus cannot be recommended as the preferred method for AAR quantification at 3.0T

Prevalence and extent of infarct and microvascular obstruction following different reperfusion therapies in ST-elevation myocardial infarction

Background: Microvascular obstruction (MVO) describes suboptimal tissue perfusion despite restoration of infarct-related artery flow. There are scarce data on Infarct Size (IS) and MVO in relation to the mode and timing of reperfusion. We sought to characterise the prevalence and extent of microvascular injury and IS using Cardiovascular magnetic resonance (CMR), in relation to the mode of reperfusion following acute ST-Elevation Myocardial Infarction (STEMI). Methods: CMR infarct characteristics were measured in 94 STEMI patients (age 61.0 ± 13.1 years) at 1.5 T. Seventy-three received reperfusion therapy: primary percutaneous coronary-intervention (PPCI, n = 47); thrombolysis (n = 12); rescue PCI (R-PCI, n = 8), late PCI (n = 6). Twenty-one patients presented late (>12 hours) and did not receive reperfusion therapy. Results: IS was smaller in PPCI (19.8 ± 13.2% of LV mass) and thrombolysis (15.2 ± 10.1%) groups compared to patients in the late PCI (40.0 ± 15.6%) and R-PCI (34.2 ± 18.9%) groups, p <0.001. The prevalence of MVO was similar across all groups and was seen at least as frequently in the non-reperfused group (15/21, [76%] v 33/59, [56%], p = 0.21) and to a similar magnitude (1.3 (0.0-2.8) v 0.4 [0.0-2.9]% LV mass, p = 0.36) compared to patients receiving early reperfusion therapy. In the 73 reperfused patients, time to reperfusion, ischaemia area at risk and TIMI grade post-PCI were the strongest independent predictors of IS and MVO. Conclusions: In patients with acute STEMI, CMR-measured MVO is not exclusive to reperfusion therapy and is primarily related to ischaemic time. This finding has important implications for clinical trials that use CMR to assess the efficacy of therapies to reduce reperfusion injury in STEMI

The REFLO-STEMI trial comparing intracoronary adenosine, sodium nitroprusside and standard therapy for the attenuation of infarct size and microvascular obstruction during primary percutaneous coronary intervention:study protocol for a randomised controlled trial

Microvascular obstruction (MVO) secondary to ischaemic-reperfusion injury is an important but underappreciated determinant of short- and longer-term outcome following percutaneous coronary intervention (PCI) treatment of ST-elevation myocardial infarction (STEMI). Several small studies have demonstrated a reduction in the degree of MVO utilising a variety of vasoactive agents, with adenosine and sodium nitroprusside (SNP) being most evaluated. However, the evidence base remains weak as the trials have had variable endpoints, differing drug doses and delivery. As such, the results regarding benefit are conflicting