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Remote ischemic preconditioning (rIPC) induced by cycles of transient limb ischemia and reperfusion is a powerful cardioprotective strategy with additional pleiotropic effects. However, our understanding of its underlying mediators and mechanisms remains incomplete. We examined the role of miR-144 in the cardioprotection induced by rIPC. Microarray studies first established that rIPC increases, and IR injury decreases miR-144 levels in mouse myocardium, the latter being rescued by both rIPC and intravenous administration of miR-144. Going along with this systemic treatment with miR-144 increased P-Akt, P-GSK3β and P-p44/42 MAPK, decreased p-mTOR level and induced autophagy signaling, and induced early and delayed cardioprotection with improved functional recovery and reduction in infarct size similar to that achieved by rIPC. Conversely, systemic administration of a specific antisense oligonucleotide reduced myocardial levels of miR-144 and abrogated cardioprotection by rIPC. We then showed that rIPC increases plasma miR-144 levels in mice and humans, but there was no change in plasma microparticle (50–400 nM) numbers or their miR-144 content. However, there was an almost fourfold increase in miR-144 precursor in the exosome pellet, and a significant increase in miR-144 levels in exosome-poor serum which, in turn, was associated with increased levels of the miR carriage protein Argonaute-2. Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC. Future studies should assess the potential for plasma miR-144 as a biomarker of the effectiveness of rIPC induced by limb ischemia, and whether miR-144 itself may represent a novel therapy to reduce clinical ischemia–reperfusion injury.

Reduction of the burden of ischaemia-reperfusion injury is the aim of most treatments for cardiovascular and cerebrovascular disease. Although many strategies have proven benefit in the experimental arena, few have translated to clinical practice. Scientific and practical reasons might explain this finding, but the unpredictability of acute ischaemic syndromes is one of the biggest obstacles to timely application of novel treatments. Remote ischaemic preconditioning—which is a powerful innate mechanism of multiorgan protection that can be induced by transient occlusion of blood flow to a limb with a blood-pressure cuff—could be close to becoming a clinical technique. Several proof-of-principle and clinical trials have been reported, suggesting that the technique has remarkable promise. We examine the history, development, and present state of remote preconditioning in cardiovascular disease.

Current cardiovascular magnetic resonance (CMR) methods, such as late gadolinium enhancement (LGE) and oedema imaging (T2W) used to depict myocardial ischemia, have limitations. Novel quantitative T1-mapping techniques have the potential to further characterize the components of ischemic injury. In patients with myocardial infarction (MI) we sought to investigate whether state-of the art pre-contrast T1-mapping (1) detects acute myocardial injury, (2) allows for quantification of the severity of damage when compared to standard techniques such as LGE and T2W, and (3) has the ability to predict long term functional recovery. 3T CMR including T2W, T1-mapping and LGE was performed in 41 patients [of these, 78% were ST elevation MI (STEMI)] with acute MI at 12-48 hour after chest pain onset and at 6 months (6M). Patients with STEMI underwent primary PCI prior to CMR. Assessment of acute regional wall motion abnormalities, acute segmental damaged fraction by T2W and LGE and mean segmental T1 values was performed on matching short axis slices. LGE and improvement in regional wall motion at 6M were also obtained. We found that the variability of T1 measurements was significantly lower compared to T2W and that, while the diagnostic performance of acute T1-mapping for detecting myocardial injury was at least as good as that of T2W-CMR in STEMI patients, it was superior to T2W imaging in NSTEMI. There was a significant relationship between the segmental damaged fraction assessed by either by LGE or T2W, and mean segmental T1 values (P < 0.01). The index of salvaged myocardium derived by acute T1-mapping and 6M LGE was not different to the one derived from T2W (P = 0.88). Furthermore, the likelihood of improvement of segmental function at 6M decreased progressively as acute T1 values increased (P < 0.0004). In acute MI, pre-contrast T1-mapping allows assessment of the extent of myocardial damage. T1-mapping might become an important complementary technique to LGE and T2W for identification of reversible myocardial injury and prediction of functional recovery in acute MI.

ObjectivesEarly detection of microvascular dysfunction after acute myocardial infarction (AMI) could identify patients at high risk of adverse clinical outcome, who may benefit from adjunctive treatment. Our objective was to compare invasively measured coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR) for their predictive power of long-term clinical outcome and cardiac magnetic resonance (CMR)-defined microvascular injury (MVI).MethodsSimultaneous intracoronary Doppler flow velocity and pressure measurements acquired immediately after revascularisation for AMI from five centres were pooled. Clinical follow-up was completed for 176 patients (mean age 60±10 years; 140(80%) male; ST-elevation myocardial infarction (STEMI) 130(74%) and non-ST-segment elevation myocardial infarction 46(26%)) with median follow-up time of 3.2 years. In 110 patients with STEMI, additional CMR was performed.ResultsThe composite end point of death and hospitalisation for heart failure occurred in 17 patients (10%). Optimal cut-off values to predict the composite end point were 1.5 for CFR and 3.0 mm Hg cm−1•s for HMR. CFR <1.5 was predictive for the composite end point (HR 3.5;95% CI 1.1 to 10.8), but not for its individual components. HMR ≥3.0 mm Hg cm−1 s was predictive for the composite end point (HR 7.0;95% CI 1.5 to 33.7) as well as both individual components. HMR had significantly greater area under the receiver operating characteristic curve for MVI than CFR. HMR remained an independent predictor of adverse clinical outcome and MVI, whereas CFR did not.ConclusionsHMR measured immediately following percutaneous coronary intervention for AMI with a cut-off value of 3.0 mm Hg cm−1 s, identifies patients with MVI who are at high risk of adverse clinical outcome. For this purpose, HMR is superior to CFR.

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  < 0.001), higher incidence and larger extent of MVO (85% vs. 40%, P  = 0.016) & [4.0 (0.5–9.5)% vs. 0 (0–3.0)%, P  = 0.025]. The average T1 value was an independent predictor of acute LGE ( β 0.61, 95%CI 0.13 to 1.09; P  = 0.015), extent of MVO ( β 0.22, 95%CI 0.03 to 0.41, P  = 0.028) and final infarct size ( β 0.63, 95%CI 0.21 to 1.05; P  = 0.005). Receiver-operating-characteristic analysis showed that T1 value of AAR obtained within 3-h, but not at 24-h, predicted large infarct size (LGE > 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.

Background It has recently been suggested that myocardial oedema follows a bimodal pattern early post ST-segment elevation myocardial infarction (STEMI). Yet, water content, quantified using tissue desiccation, did not return to normal values unlike oedema quantified by cardiovascular magnetic resonance (CMR) imaging. We studied the temporal changes in the extent and intensity of injured myocardium using T1-mapping technique within the first week after STEMI. Methods A first group ( n  = 31) underwent 3 acute 3 T CMR scans (time-point (TP) < 3 h, 24 h and 6 days), including cine, native shortened modified look-locker inversion recovery T1 mapping, T2* mapping and late gadolinium enhancement (LGE). A second group ( n  = 17) had a single scan at 24 h with an additional T2-weighted sequence to assess the difference in the extent of area-at-risk (AAR) compared to T1-mapping. Results The mean T1 relaxation time value within the AAR of the first group was reduced after 24 h ( P  < 0.001 for TP1 vs.TP2) and subsequently increased at 6 days ( P  = 0.041 for TP2 vs.TP3). However, the extent of AAR quantified using T1-mapping did not follow the same course, and no change was detected between TP1&TP2 ( P  = 1.0) but was between TP2 &TP3 ( P  = 0.019). In the second group, the extent of AAR was significantly larger on T1-mapping compared to T2-weighted (42 ± 15% vs. 39 ± 15%, P  = 0.025). No change in LGE was detected while microvascular obstruction and intra-myocardial haemorrhage peaked at different time points within the first week of reperfusion. Conclusion The intensity of oedema post-STEMI followed a bimodal pattern; while the extent of AAR did not track the same course. This discrepancy has implications for use of CMR in this context and may explain the previously reported disagreement between oedema quantified by imaging and tissue desiccation.

Thorough reanalysis of available data found that the strong links between the splenic signal intensity change and delta spleen T1, and the ability of delta spleen T1 to predict the splenic switch-off sign, could not be independently reproduced, although the general observations reported in Table 2 (that the spleen T1 decreases significantly in response to Adenosine) and inter-observer reproducibility of delta spleen T1 could be reproduced. [...]of the information available, the Editor-in-Chief advises readers to interpret the results of this publication with due caution. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Thorough reanalysis of available data found that the strong links between the splenic signal intensity change and delta spleen T1, and the ability of delta spleen T1 to predict the splenic switch-off sign, could not be independently reproduced, although the general observations reported in Table 2 (that the spleen T1 decreases significantly in response to Adenosine) and inter-observer reproducibility of delta spleen T1 could be reproduced. [...]of the information available, the Editor-in-Chief advises readers to interpret the results of this publication with due caution.

Background FFR is routinely used to guide percutaneous coronary interventions (PCI). Visual assessment of the angiographic result after PCI has limited efficacy. Even when the angiographic result seems satisfactory FFR after a PCI might be useful for identifying patients with a suboptimal interventional result and higher risk for poor clinical outcome who might benefit from additional procedures. The aim of this meta-analysis was to investigate available data of studies that examined clinical outcomes of patients with impaired vs. satisfactory fractional flow reserve (FFR) after percutaneous coronary interventions (PCI). Methods This meta-analysis was carried out according to the Cochrane Handbook for Systematic Reviews. The Mantel-Haenszel method using the fixed-effect meta-analysis model was used for combining the results. Studies were identified by searching the literature through mid-January, 2016, using the following search terms: fractional flow reserve, coronary circulation, after, percutaneous coronary intervention, balloon angioplasty, stent implantation, and stenting. Primary endpoint was the rate of major adverse cardiac events (MACE). Secondary endpoints included rates of death, myocardial infarction (MI), repeated revascularisation. Results Eight relevant studies were found including a total of 1337 patients. Of those, 492 (36.8 %) had an impaired FFR after PCI, and 853 (63.2 %) had a satisfactory FFR after PCI. Odds ratios indicated that a low FFR following PCI was associated with an impaired outcome: major adverse cardiac events (MACE, OR: 4.95, 95 % confidence interval [CI]: 3.39–7.22, p < 0.001); death (OR: 3.23, 95 % CI: 1.19–8.76, p  = 0.022); myocardial infarction (OR: 13.83, 95 % CI: 4.75–40.24, p <0.0001) and repeated revascularisation (OR: 4.42, 95 % CI: 2.73–7.15, p <0.0001). Conclusions Compared to a satisfactory FFR, a persistently low FFR following PCI is associated with a worse clinical outcome. Prospective studies are needed to identify underlying causes, determine an optimal threshold for post-PCI FFR, and clarify whether simple additional procedures can influence the post-PCI FFR and clinical outcome.

Assessment of coronary stenosis severity is crucial in clinical practice. This study proposes a novel method to generate 3D models of stenotic coronary arteries, directly from 2D coronary images, and suitable for immediate assessment of the stenosis severity. From multiple 2D X-ray coronary arteriogram projections, 2D vessels were extracted. A 3D centreline was reconstructed as intersection of surfaces from corresponding branches. Next, 3D luminal contours were generated in a two-step process: first, a Non-Uniform Rational B-Spline (NURBS) circular contour was designed and, second, its control points were adjusted to interpolate computed 3D boundary points. Finally, a 3D surface was generated as an interpolation across the control points of the contours and used in the analysis of the severity of a lesion. To evaluate the method, we compared 3D reconstructed lesions with Optical Coherence Tomography (OCT), an invasive imaging modality that enables high-resolution endoluminal visualization of lesion anatomy. Validation was performed on routine clinical data. Analysis of paired cross-sectional area discrepancies indicated that the proposed method more closely represented OCT contours than conventional approaches in luminal surface reconstruction, with overall root-mean-square errors ranging from 0.213mm2 to 1.013mm2, and maximum error of 1.837mm2. Comparison of volume reduction due to a lesion with corresponding FFR measurement suggests that the method may help in estimating the physiological significance of a lesion. The algorithm accurately reconstructed 3D models of lesioned arteries and enabled quantitative assessment of stenoses. The proposed method has the potential to allow immediate analysis of the stenoses in clinical practice, thereby providing incremental diagnostic and prognostic information to guide treatments in real time and without the need for invasive techniques.

Nearly half of all patients with angina have non-obstructive coronary artery disease (ANOCA); this is an umbrella term comprising heterogeneous vascular disorders, each with disparate pathophysiology and prognosis. Approximately two-thirds of patients with ANOCA have coronary microvascular disease (CMD). CMD can be secondary to architectural changes within the microcirculation or secondary to vasomotor dysfunction. An inability of the coronary vasculature to augment blood flow in response to heightened myocardial demand is defined as an impaired coronary flow reserve (CFR), which can be measured non-invasively, using imaging, or invasively during cardiac catheterisation. Impaired CFR is associated with myocardial ischaemia and adverse cardiovascular outcomes.The CMD workstream is part of the cardiovascular partnership between the British Heart Foundation and The National Institute for Health Research in the UK and comprises specialist cardiac centres with expertise in coronary physiology assessment. This document outlines the two main modalities (thermodilution and Doppler techniques) for estimation of coronary flow, vasomotor testing using acetylcholine, and outlines a standard operating procedure that could be considered for adoption by national networks. Accurate and timely disease characterisation of patients with ANOCA will enable clinicians to tailor therapy according to their patients’ coronary physiology. This has been shown to improve patients’ quality of life and may lead to improved cardiovascular outcomes in the long term.