Why, When and How Should Clinicians Use Physiology in Patients with Acute Coronary Syndromes?

Current data support the use of coronary physiology in patients with acute coronary syndrome (ACS). In patients with ST-elevation MI, the extent of myocardial damage and microvascular dysfunction create a complex conundrum to assimilate when considering clinical management and risk stratification. In this setting, the index of microcirculatory resistance emerged as an accurate tool to identify patients at risk of suboptimal myocardial reperfusion after primary percutaneous coronary intervention who may benefit from novel adjunctive therapies. In the context of non-ST-elevation ACS, coronary physiology should be carefully interpreted and often integrated with intracoronary imaging, especially in cases of ambiguous culprit lesion. Conversely, the functional assessment of bystander coronary disease is favoured by the available evidence, aiming to achieve complete revascularisation. Based on everyday clinical scenarios, the authors illustrate the available evidence and provide recommendations for the functional assessment of infarct-related artery and non-culprit lesions in patients with ACS

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management

Angiography-derived index of microcirculatory resistance as a novel, pressure-wire-free tool to assess coronary microcirculation in ST elevation myocardial infarction

Immediate assessment of coronary microcirculation during treatment of ST elevation myocardial infarction (STEMI) may facilitate patient stratification for targeted treatment algorithms. Use of pressure-wire to measure the index of microcirculatory resistance (IMR) is possible but has inevitable practical restrictions. We aimed to develop and validate angiography-derived index of microcirculatory resistance (IMRangio) as a novel and pressure-wire-free index to facilitate assessment of the coronary microcirculation. 45 STEMI patients treated with primary percutaneous coronary intervention (pPCI) were enrolled. Immediately before stenting and at completion of pPCI, IMR was measured within the infarct related artery (IRA). At the same time points, 2 angiographic views were acquired during hyperaemia to measure quantitative flow ratio (QFR) from which IMRangio was derived. In a subset of 15 patients both IMR and IMRangio were also measured in the non-IRA. Patients underwent cardiovascular magnetic resonance imaging (CMR) at 48 h for assessment of microvascular obstruction (MVO). IMRangio and IMR were significantly correlated (rho: 0.85, p < 0.001). Both IMR and IMRangio were higher in the IRA rather than in the non-IRA (p = 0.01 and p = 0.006, respectively) and were higher in patients with evidence of clinically significant MVO (> 1.55% of left ventricular mass) (p = 0.03 and p = 0.005, respectively). Post-pPCI IMRangio presented and area under the curve (AUC) of 0.96 (CI95% 0.92-1.00, p < 0.001) for prediction of post-pPCI IMR > 40U and of 0.81 (CI95% 0.65-0.97, p < 0.001) for MVO > 1.55%. IMRangio is a promising tool for the assessment of coronary microcirculation. Assessment of IMR without the use of a pressure-wire may enable more rapid, convenient and cost-effective assessment of coronary microvascular function

Individual patient-data meta-analysis comparing clinical outcome in patients with ST-elevation myocardial infarction treated with percutaneous coronary intervention with or without prior thrombectomy. ATTEMPT study: A pooled Analysis of Trials on ThrombEctomy in acute Myocardial infarction based on individual PatienT data

Background: Available data from randomized trials on thrombectomy in patients with ST-elevation myocardial infarction (STEMI) have shown favorable trends in myocardial reper-fusion. However, few data are available on the effect of thrombectomy on clinical outcome. Thus we have designed a collaborative individual patient-data meta-analysis which aimed to assess the long-term clinical outcome in STEMI patients randomized to percutaneous coronary intervention (PCI) with or without thrombectomy. Method: After a thorough database search, the principal investigators of randomized trials comparing thrombectomy with standard PCI in patients with STEMI were contacted. Principal investigators as authors of 11 randomized studies agreed to participate and were asked to complete a structured database by providing a series of key pre-PCI clinical and angiographic data as well as the longest available clinical outcome of the patients enrolled in the corresponding trial. The primary end-point of this pooled analysis is the comparison of overall survival rates between patients randomized to PCI with thrombectomy or PCI without thrombectomy. The secondary end-points are survival free from myocardial infarction (MI), target lesion revascularization (TLR), major adverse coronary events (MACE: death + MI + TLR) and death + MI between patients randomized to PCI with thrombectomy or PCI without thrombectomy. A pre-defined subgroup analysis is planned considering the following variables: type of thrombectomy device used, diabetes, rescue PCI, IIb/IIIa-inhibitors use, time-to-reperfusion, infarct-related artery, and pre-PCI TIMI flow. Implications: This study will provide useful data on the effect of the reported improved myocardial perfusion associated with thrombectomy on the long-term clinical outcome in patients with STEMI. © 2009 De Vita et al, publisher and licensee Dove Medical Press Ltd

Hyper-acute cardiovascular magnetic resonance T1 mapping predicts infarct characteristics in patients with ST elevation myocardial infarction

Background Myocardial recovery after primary percutaneous coronary intervention in acute myocardial infarction is variable and the extent and severity of injury are difficult to predict. We sought to investigate the role of cardiovascular magnetic resonance T1 mapping in the determination of myocardial injury very early after treatment of ST-segment elevation myocardial infarction (STEMI). Methods STEMI patients underwent 3 T cardiovascular magnetic resonance (CMR), within 3 h of primary percutaneous intervention (PPCI). T1 mapping determined the extent (area-at-risk as %left ventricle, AAR) and severity (average T1 values of AAR) of acute myocardial injury, and related these to late gadolinium enhancement (LGE), and microvascular obstruction (MVO). The characteristics of myocardial injury within 3 h was compared with changes at 24-h to predict final infarct size. Results Forty patients were included in this study. Patients with average T1 values of AAR ≥1400 ms within 3 h of PPCI had larger LGE at 24-h (33% ±14 vs. 18% ±10, P = 0.003) and at 6-months (27% ±9 vs. 12% ±9; P  9.5%) with 100% positive predictive value at the optimal cut-off of 1400 ms (area-under-the-curve, AUC 0.88, P = 0.006). Conclusion Hyper-acute T1 values of the AAR (within 3 h post PPCI, but not 24 h) predict a larger extent of MVO and infarct size at both 24 h and 6 months follow-up. Delayed CMR scanning for 24 h could not substitute the significant value of hyper-acute average T1 in determining infarct characteristics

Crude incidence in two-phase designs in the presence of competing risks.

BackgroundIn many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome.MethodsWe develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard.ResultsThe proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care.ConclusionsA valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived

Determination of copper and alcohol contents in sugar cane spirits produced in the state of Minas Gerais, Brazil.

The objective of this work was to investigate if producers of sugar cane spirits in Minas Gerais, Brazil, have improved the copper content of their products and also if they have adjusted to the new standards of identity for ?cacha?a? and ?aguardente?. Seventy-one samples, obtained from May 2003 until March 2004, were analyzed. Mean copper content was 2.30 mg/L, which indicates a significant reduction in levels. The mean alcohol content was 45.6 % v/v. All of the ?aguardente? but only 79% of the ?cacha?a? attended to the standard of identity for alcohol content for these products

New ammonia lyases and amine transaminases: Standardization of production process and preparation of immobilized biocatalysts

Background: New enzymes for biotransformations can be obtained by different approaches including directed mutagenesis and in vitro evolution. These mutants have to be efficiently produced for laboratory research on bioreactions as well as for process development. In the framework of a European ERA-IB project, two different types of enzymes (ammonia lyases and aminotransferases) have been selected as biocatalysts for the synthesis of industrially relevant amines. New mutant enzymes have been obtained: a) aspartases able to recognize \u3b2-amino acids; b) \u3c9-transaminases with improved activity. The objectives are to find out a common operational strategy applicable to different mutants expressed in E. coli with the same initial genetic background, the development of an integrated process for production and the preparation of stable useful biocatalysts. Results: Mutant enzymes were expressed in E. coli BL21 under the control of isopropylthiogalactoside (IPTG) inducible promoter. The microorganisms were grown in a formulated defined medium and a high-cell density culture process was set up. Fed-batch operation at constant specific growth rate, employing an exponential addition profile allowed high biomass concentrations. The same operational strategy was applied for different mutants of both aspartase and transaminase enzymes, and the results have shown a common area of satisfactory operation for maximum production at low inducer concentration, around 2 \u3bcmol IPTG/g DCW. The operational strategy was validated with new mutants and high-cell density cultures were performed for efficient production. Suitable biocatalysts were prepared after recovery of the enzymes. The obtained aspartase was immobilized by covalent attachment on MANA-agarose, while \u3c9-transaminase biocatalysts were prepared by entrapping whole cells and partially purified enzyme onto Lentikats (polyvinyl alcohol gel lens-shaped particles). Conclusions: The possibility of expressing different mutant enzymes under similar operation conditions has been demonstrated. The process was standardized for production of new aspartases with \u3b2-amino acid selectivity and new \u3c9-transaminases with improved substrate acceptance. A whole process including production, cell disruption and partial purification was set up. The partially purified enzymes were immobilized and employed as stable biocatalysts in the synthesis of chiral amines