Objective: To investigate the relative importance of stent induced arterial stretch and deep injury to the development of in-stent neointima. Setting: Normal porcine coronary arteries Methods: 30 BiodivYsio stents (Biocompatibles) were deployed at a stent to artery ratio of 1.25:1 (a moderate injury) and harvested at 28 days. Multiple serial cross sections were analysed morphometrically and the neointimal areas were correlated with the type and degree of injury. Results: Arterial stretch occurred in 78% of struts (77% of sections) and produced moderate neointimal growth (neointimal area 1.93 (0.13) mm²). Deep injury (rupture of the internal elastic lamina) occurred in 20% of struts (23% of sections) and produced a 1.7-fold increase in neointimal area (3.33 (0.41) mm²) compared with stretch only (p = 0.0002). With even deeper injury (rupture of the external elastic lamina), there was a 2.6-fold increase in neointimal area (5.01 (0.48) mm²) compared with stretch only (p = 0.02). A new injury score, incorporating both stretch and deep injury, correlated with neointimal area (r = 0.60, p < 0.001). Conclusions: Stretch of the coronary artery in a stent is common, and a major contributor to neointima formation, even in the absence of deep injury. Deep injury is, however, a more potent stimulus to neointima formation than stretch. Greater degrees of stretch are associated with thicker neointima. Where neither deep injury nor stretch are seen, the stent has no effect upon the development of neointima.

Acute Coronary Syndromes account for 15% of deaths in the UK, and patients remain at significant risk of re-admission for future complications and death. Pathologically the underlying process of atherosclerosis is driven by inflammatory mechanisms, which are activated in ACS patients. Previous studies have investigated the role of inflammatory markers in this process, including interleukin 1 (IL-1) and C Reactive Protein (CRP). Pre-clinical studies indicate that IL-1 may be a primary driver of ACS and that the naturally occurring interleukin-1 receptor antagonist (IL-1ra) may inhibit the atherosclerotic process. This study will investigate the effects of IL-1ra on inflammatory markers in man. Three centres in the UK are planning to recruit 186 Non-ST elevation myocardial infarction patients to receive either interleukin-1 receptor antagonist (Anakinra) or matching placebo. Patients will receive a daily subcutaneous injection of either study drug or placebo over a 14 day period. The primary outcome is area under the curve of high sensitivity C-Reactive Protein (CRP) over the first 7 days. The MRC-ILA-HEART Study is a proof of concept clinical trial investigating the effects of IL-1ra upon markers of inflammation in patients with Non-ST elevation myocardial infarction. It is hoped this will provide new and exciting information in relation to an "anti-inflammatory" strategy for patients with acute coronary syndrome. ISRCTN89369318

Ischaemic heart disease is the reduction of myocardial blood flow, caused by epicardial and/or microvascular disease. Both are common and prognostically important conditions, with distinct guideline-indicated management. Fractional flow reserve (FFR) is the current gold-standard assessment of epicardial coronary disease but is only a surrogate of flow and only predicts percentage flow changes. It cannot assess absolute (volumetric) flow or microvascular disease. The aim of this study was to develop and validate a novel method that predicts absolute coronary blood flow and microvascular resistance (MVR) in the catheter laboratory. A computational fluid dynamics (CFD) model was used to predict absolute coronary flow (Q_CFD) and coronary MVR using data from routine invasive angiography and pressure-wire assessment. Q_CFD was validated in an in vitro flow circuit which incorporated patient-specific, three-dimensional printed coronary arteries; and then in vivo, in patients with coronary disease. In vitro, Q_CFD agreed closely with the experimental flow over all flow rates [bias +2.08 mL/min; 95% confidence interval (error range) −4.7 to +8.8 mL/min; R² = 0.999, P < 0.001; variability coefficient <1%]. In vivo, Q_CFD and MVR were successfully computed in all 40 patients under baseline and hyperaemic conditions, from which coronary flow reserve (CFR) was also calculated. Q_CFD-derived CFR correlated closely with pressure-derived CFR (R² = 0.92, P < 0.001). This novel method was significantly more accurate than Doppler-wire-derived flow both in vitro (±6.7 vs. ±34 mL/min) and in vivo (±0.9 vs. ±24.4 mmHg). Absolute coronary flow and MVR can be determined alongside FFR, in absolute units, during routine catheter laboratory assessment, without the need for additional catheters, wires or drug infusions. Using this novel method, epicardial and microvascular disease can be discriminated and quantified. This comprehensive coronary physiological assessment may enable a new level of patient stratification and management.

Proto-oncogenes, including c- myb , are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN–c- myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN–c- myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c- myb mRNA and protein. Expression of another early gene, c- fos , was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN–c- myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c- myb , with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN–c- myb was 30 times less potent than unphosphorothioated AS-ODN–c- myb . PTCA induced porcine coronary artery neointima formation. c -myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN–c- myb , sense-ODN–c- myb , saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN–c- myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN–c- myb by 79% compared with saline ( P <.05), 82% compared with sense-ODN–c- myb , and 63% compared with nothing ( P <.10). Conclusions are as follows: (1) c- myb is expressed in VSMCs after vascular injury. (2) AS-ODN–c- myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c- myb mRNA and protein, whereas sense-ODN–c- myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non–sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN – c- myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening.

Recent efforts have demonstrated the ability of computational models to predict fractional flow reserve from coronary artery imaging without the need for invasive instrumentation. However, these models include only larger coronary arteries as smaller side branches cannot be resolved and are therefore neglected. The goal of this study was to evaluate the impact of neglecting the flow to these side branches when computing angiography-derived fractional flow reserve (vFFR) and indices of volumetric coronary artery blood flow. To compensate for the flow to side branches, a leakage function based upon vessel taper (Murray's Law) was added to a previously developed computational model of coronary blood flow. The augmented model with a leakage function (1Dleaky) and the original model (1D) were then applied to predict FFR as well as inlet and outlet flow in 146 arteries from 80 patients who underwent invasive coronary angiography and FFR measurement. The results show that the leakage function did not significantly change the vFFR but did significantly impact the estimated volumetric flow rate and predicted coronary flow reserve. As both procedures achieved similar predictive accuracy of vFFR despite large differences in coronary blood flow, these results suggest careful consideration of the application of this index for quantitatively assessing flow.