Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Association of MicroRNAs and YRNAs With Platelet Function.

RATIONALE: Platelets shed microRNAs (miRNAs). Plasma miRNAs change on platelet inhibition. It is unclear whether plasma miRNA levels correlate with platelet function. OBJECTIVE: To link small RNAs to platelet reactivity. METHODS AND RESULTS: Next-generation sequencing of small RNAs in plasma revealed 2 peaks at 22 to 23 and 32 to 33 nucleotides corresponding to miRNAs and YRNAs, respectively. Among YRNAs, predominantly, fragments of RNY4 and RNY5 were detected. Plasma miRNAs and YRNAs were measured in 125 patients with a history of acute coronary syndrome who had undergone detailed assessment of platelet function 30 days after the acute event. Using quantitative real-time polymerase chain reactions, 92 miRNAs were assessed in patients with acute coronary syndrome on different antiplatelet therapies. Key platelet-related miRNAs and YRNAs were correlated with platelet function tests. MiR-223 (rp=0.28; n=121; P=0.002), miR-126 (rp=0.22; n=121; P=0.016), and other abundant platelet miRNAs and YRNAs showed significant positive correlations with the vasodilator-stimulated phosphoprotein phosphorylation assay. YRNAs, miR-126, and miR-223 were also among the small RNAs showing the greatest dependency on platelets and strongly correlated with plasma levels of P-selectin, platelet factor 4, and platelet basic protein in the population-based Bruneck study (n=669). A single-nucleotide polymorphism that facilitates processing of pri-miR-126 to mature miR-126 accounted for a rise in circulating platelet activation markers. Inhibition of miR-126 in mice reduced platelet aggregation. MiR-126 directly and indirectly affects ADAM9 and P2Y12 receptor expression. CONCLUSIONS: Levels of platelet-related plasma miRNAs and YRNAs correlate with platelet function tests in patients with acute coronary syndrome and platelet activation markers in the general population. Alterations in miR-126 affect platelet reactivity.

When is rotational angiography superior to conventional single-plane angiography for planning coronary angioplasty?

OBJECTIVES: To investigate the value of rotational coronary angiography (RoCA) in the context of percutaneous coronary intervention (PCI) planning. BACKGROUND: As a diagnostic tool, RoCA is associated with decreased patient irradiation and contrast use compared with conventional coronary angiography (CA) and provides superior appreciation of three-dimensional anatomy. However, its value in PCI remains unknown. METHODS: We studied stable coronary artery disease assessment and PCI planning by interventional cardiologists. Patients underwent either RoCA or conventional CA pre-PCI for planning. These were compared with the referral CA (all conventional) in terms of quantitative lesion assessment and operator confidence. An independent panel reanalyzed all parameters. RESULTS: Six operators performed 127 procedures (60 RoCA, 60 conventional CA, and 7 crossed-over) and assessed 212 lesions. RoCA was associated with a reduction in the number of lesions judged to involve a bifurcation (23 vs. 30 lesions, P < 0.05) and a reduction in the assessment of vessel caliber (2.8 vs. 3.0 mm, P < 0.05). RoCA improved confidence assessing lesion length (P = 0.01), percentage stenosis (P = 0.02), tortuosity (P < 0.04), and proximity to a bifurcation (P = 0.03), particularly in left coronary artery cases. X-ray dose, contrast agent volume, and procedure duration were not significantly different. CONCLUSIONS: Compared with conventional CA, RoCA augments quantitative lesion assessment, enhances confidence in the assessment of coronary artery disease and the precise details of the proposed procedure, but does not affect X-ray dose, contrast agent volume, or procedure duration.

The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study.

AIMS: Acute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS. METHODS AND RESULTS: A phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31-29.64); placebo group, 43.5 mg day/L (31.15-60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32-0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65-4.62): placebo; 2.21 mg/L (1.67-2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group. CONCLUSION: IL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety. CLINICAL TRIAL REGISTRATION EUCTR: 2006-001767-31-GB: www.clinicaltrialsregister.eu/ctr-search/trial/2006-001767-31/GB.

Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes.

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y12 inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20 µM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57 ± 18%, 41 ± 20%, and 31 ± 12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel (p < 0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel (p = 0.015) and clopidogrel (p < 0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y12 inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y12 inhibition than both clopidogrel and prasugrel during maintenance therapy.

Impact of incomplete revascularization in patients undergoing PCI for unprotected left main stem stenosis.

INTRODUCTION: Percutaneous revascularization of patients with multivessel and left main stem (LMS) disease may be incomplete and the impact of this is not well reported and may influence outcome. In this study we assessed the role of completeness of revascularization upon outcome after PCI for unprotected left main stem (uLMS) PCI in the "real world." MATERIALS AND METHOD: Consecutive patients (n = 353) with uLMS disease were treated by PCI by a single operator with a policy of maximal feasible revascularization between 2000 and 2011. The SYNTAX score was calculated before and after PCI (residual SYNTAX score) to gauge the completeness of revascularization. The endpoints were mortality and repeat revascularization. RESULTS: Mean age was 69 ± 11 years, baseline SYNTAX score was 33.4 ± 15, 53% were nonelective, 10% were in cardiogenic shock, and 45% were not surgical candidates. LMS bifurcation was involved in 74% and 2.0 ± 0.9 other vessels were diseased. Complete revascularization was achieved in 49% and was associated with reduced mortality compared with incomplete, at 30 days [5(2.9%) v 23(13%)], 1 year [9(5%) v 34(19%)], and 3 years [14(8%) v 46(26%)]; all P < 0.0001). Median rSYNTAX score was 1(0-11), 1-year survival for the lowest, middle and highest tertiles of rSYNTAX were 1.7%, 3.1% and 7.3% (P < 0.0001), respectively. In multivariate analysis postprocedure rSYNTAX score independently predicted outcome but preprocedural SYNTAX score did not. CONCLUSIONS: For unselected patients with uLMS treated by PCI, completeness of revascularization is associated with superior survival. The rSYNTAX score, a novel index of completeness of revascularization, independently predicts survival. Baseline SYNTAX score does not.

Novel use of a pericardium-covered stent graft to treat bulky coronary artery thrombus.

OBJECTIVES: We studied the acute safety and feasibility of a pericardium-covered stent (PCS) in the obliteration of massive coronary thrombus. BACKGROUND: Thrombus is frequently encountered in the setting of acute myocardial infarction, and conventional pharmacological and aspiration approaches are not always successful in dispersing or removing it, especially when it is very substantial. METHODS: We treated nine patients (10 lesions) in the setting of an acute coronary syndrome characterized by the presence of substantial (TIMI grade 3-4) thrombus in a large caliber native coronary artery, persisting after conventional treatment, with percutaneous implantation of an equine PCS graft. Nine of 10 lesions were in large right coronary arteries. RESULTS: Deployment was successful in nine of 10 lesions. In all nine cases, the filling defect was immediately eliminated and there was restoration or maintenance of TIMI grade 3 blood flow. There was one in-hospital stent thrombosis in a 56-year-old male, who had only received aspirin due to a coexistent stroke. This patient underwent successful repeat percutaneous intervention but died later of complications of the stroke. There were no 30-day events, and medium-term follow-up continues. CONCLUSIONS: A PCS graft is a potentially useful device to treat massive thrombus burden in the setting of acute coronary syndrome. A larger study is warranted.

The effects of low-level laser therapy in a rat model of intestinal ischemia-reperfusion injury.

BACKGROUND AND OBJECTIVE: To investigate the effects of low-level laser therapy applied to the serosal surface of the rat jejunum following ischemia and reperfusion. MATERIALS AND METHODS: Ninety-six male Sprague-Dawley rats were assigned to 15 groups and anesthetized. Small intestinal ischemia was induced by clamping the superior mesenteric artery for 60 minutes. A laser diode (70 mW, 650 nm) was applied to the serosal surface of the jejunum at a dose of 0.5 J/cm(2) either immediately before or following initiation of reperfusion. Animals were maintained under anesthesia and sacrificed at 0, 1, and 6 hours following reperfusion. Intestinal, lung, and liver samples were evaluated histologically. RESULTS: Intestinal injury was significantly worse (P < 0.0001) in animals treated with laser and no ischemia-reperfusion injury (IRI) compared to sham. Intestinal injury was significantly worse in animals that underwent IRI and laser treatment at all time points compared to sham (P < 0.001). In animals that underwent IRI, those treated with laser had significantly worse intestinal injury compared to those that did not have laser treatment at 0 (P = 0.0104) and 1 (P = 0.0015) hour of reperfusion. After 6 hours of reperfusion there was no significant difference in injury between these two groups. Lung injury was significantly decreased following IRI in laser-treatment groups (P < 0.001). CONCLUSIONS: At the dose and parameters used, low-level laser did not protect against intestinal IRI in the acute phase of injury. However, laser did provide protection against distant organ injury. Failure to observe a therapeutic response in the intestine may be due to inappropriate dosing parameters. Furthermore, the model was designed to detect the histologic response within the first 6 hours of injury, whereas the beneficial effects of laser, if they occur, may not be observed until the later phases of healing. The finding of secondary organ protection is important, as lung injury following IRI is a significant source of morbidity and mortality.

Rare Association between Giant Right Ventricular Myxoma and Right Coronary Artery Tumour Blush with Complicating Pulmonary Tumour Embolism.

Cardiac myxoma is a benign primary cardiac tumour which can present with nonspecific symptoms of right heart failure, syncope, exertional dyspnea, and pulmonary embolism. We describe a case of a right ventricular myxoma complicated with bilateral pulmonary embolism, with an incidental right coronary artery fistula but otherwise normal coronary anatomy on coronary angiogram. This case report emphasizes the importance of performing a transesophageal echo in the setting of pulmonary embolism to search for the origin of thrombus/tumour, and performing a comprehensive assessment is also necessary to rule out coronary artery disease, coronary artery fistula that may also represent a tumour blush.

Interleukin-1 receptor antagonist alters the response to vessel wall injury in a porcine coronary artery model.

OBJECTIVE: To determine the influence of IL-1 on the arterial response to experimental injury in porcine models of percutaneous coronary intervention (PCI). METHODS: An intravenous (i.v.) bolus of 0.5 mg/kg followed by a subcutaneous (s.c.) infusion of 2 mg/kg/24 h of human IL-1 receptor antagonist (IL-1ra) inhibited neutrophil recruitment in response to intradermal IL-1. Using this dose regimen, five groups of pigs were studied: Group 1, oversized balloon angioplasty of 2 coronary vessels (14-day infusion, 28th day sacrifice and analysis); Groups 2, 3, 4, and 5, oversized stenting of 2 coronary vessels (Group 2: 14-day infusion, 28th day analysis; Group 3: 14-day infusion, 14th day analysis; Group 4: 28-day infusion, 28th day analysis; Group 5: 28-day infusion, 90th day analysis). Neointimal area was quantified by standard means. RESULTS: In Group 1, IL-1ra resulted in a 23% decrease in neointimal area (p=0.04); in Group 2, a 34% increase (p=0.001); in Group 3, a 38% decrease (p<0.0001); in Group 4, a 34% decrease (p=0.0004); and in Group 5, a 41% decrease (p=0.00001). CONCLUSIONS: IL-1ra was associated with a sustained, significant reduction in neointima after vessel wall injury as long as it is given for the duration of the stimulation of the IL-1 system, in this case at least 28 days. This suggests that therapies based on the antagonism of IL-1 may modulate the coronary artery response to injury.

Antithrombotic therapy in patients with combined coronary heart disease and atrial fibrillation.

Coronary heart disease (CHD) and atrial fibrillation (AF) commonly occur together. This presents challenges for the clinician treating patients with CHD, who require antiplatelet therapy and patients with AF, who require oral anticoagulant therapy. We have reviewed PubMed and SCOPUS to identify relevant guidelines, randomised clinical trials and registry studies and clinical trials presented at international meetings, and where necessary, clinical trial protocols to identify and critically analyze all relevant trials in which combinations of oral anticoagulants and antiplatelet agents in patients with AF and CHD have been evaluated. The available evidence on the efficacy and safety of combined oral anticoagulants and anti platelet agents was reviewed for the AF patient in three clinical scenarios: 1) after percutaneous coronary intervention (PCI); 2) after an acute coronary syndrome without PCI; and 3) in stable CHD. In each the clinical scenarios evaluated, there is limited clinical trial evidence to guide clinical management. Guidelines to help the clinician choose the right combinations of warfarin, clopidogrel and aspirin and the duration of treatment have been published, but they are based on a limited evidence base. There is even less evidence to guide the use of new oral anticoagulants (NOACs) in combination with the new P2Y12 antiplatelet agents. In each clinical scenario, the risks of coronary artery or stent thrombosis in CHD and risks of stroke in AF need to be carefully balanced against the risks of bleeding. We make recommendations for management based on the evidence which is available at this time and indicate the many gaps which are currently being addressed by randomized clinical trials.

Morphine delays the onset of action of prasugrel in patients with prior history of ST-elevation myocardial infarction.

Delays in the onset of action of prasugrel during primary percutaneous coronary intervention (PPCI) have been reported and could be related to the effects of morphine on gastric emptying and subsequent intestinal absorption. The study objective was to determine whether morphine delays the onset of action of prasugrel in patients with a prior history of ST-elevation myocardial infarction (STEMI) treated with PPCI. This was a crossover study of 11 aspirin-treated patients with prior history of STEMI treated with PPCI, for which prasugrel and morphine had been previously administered. Patients were randomised to receive either morphine (5 mg) or saline intravenously followed by 60 mg prasugrel. Blood samples were collected before randomised treatment and over 24 hours after prasugrel administration. The inhibitory effects of prasugrel on platelets were determined using the VerifyNow P2Y12 assay and light transmission aggregometry. Plasma levels of prasugrel and prasugrel active metabolite were measured. Platelet reactivity determined by VerifyNow PRU, VerifyNow % Inhibition and LTA was significantly higher at 30-120 minutes (min) when morphine had been co-administered compared to when saline had been co-administered. Morphine, compared to saline, significantly delayed adequate platelet inhibition after prasugrel administration (158 vs 68 min; p = 0.006). Patients with delayed onset of platelet inhibition also had evidence of delayed absorption of prasugrel. In conclusion, prior administration of intravenous morphine significantly delays the onset of action of prasugrel. Intravenous drugs may be necessary to reduce the risk of acute stent thrombosis in morphine-treated STEMI patients undergoing PPCI.

Percutaneous brachial artery access for coronary artery procedures: Feasible and safe in the current era.

BACKGROUND: Percutaneous vascular access for coronary intervention is currently achieved predominately via the radial route, the femoral route acting as a backup. Percutaneous trans-brachial access is no longer commonly used due to concerns about vascular complications. This study aimed to investigate the safety and feasibility of percutaneous brachial access when femoral and radial access was not possible. METHODS: This is a retrospective data analysis of patients who attended a single tertiary cardiology centre in the UK between 2005 and 2014 and had a coronary intervention (coronary angiogram or PCI) via the brachial route. The primary endpoints were procedural success and the occurrence of vascular complications. RESULTS: During the study period 26602 patients had a procedure (15655 underwent PCI and 10947 diagnostic angiography). Of these, 117 (0.44% of total) had their procedure performed via the brachial route. The procedure was successful in 96% (112/117) of cases. 13 (11%) patients experienced post procedural complications, of which 2 (1.7%) were serious. There were no deaths. CONCLUSION: Percutaneous trans-brachial arterial access is feasible with a high success rate and without evidence of high complication rate in a rare group of patients in whom femoral or sometimes radial attempts have failed.

Elevated plasma CXCL12α is associated with a poorer prognosis in pulmonary arterial hypertension.

RATIONALE: Recent work in preclinical models suggests that signalling via the pro-angiogenic and pro-inflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortality. METHODS: Plasma samples were collected from patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with connective tissue diseases (CTD-PAH) attending two pulmonary hypertension referral centres (n = 95) and from age and gender matched healthy controls (n = 44). Patients were subsequently monitored throughout a period of five years. RESULTS: CXCL12α concentrations were elevated in PAH groups compared to controls (P<0.05) and receiver-operating-characteristic analysis showed that plasma CXCL12α concentrations discriminated patients from healthy controls (AUC 0.80, 95% confidence interval 0.73-0.88). Kaplan Meier analysis indicated that elevated plasma CXCL12α concentration was associated with reduced survival (P<0.01). Multivariate Cox proportional hazards model showed that elevated CXCL12α independently predicted (P<0.05) earlier death in PAH with a hazard ratio (95% confidence interval) of 2.25 (1.01-5.00). In the largest subset by WHO functional class (Class 3, 65% of patients) elevated CXCL12α independently predicted (P<0.05) earlier death, hazard ratio 2.27 (1.05-4.89). CONCLUSIONS: Our data show that elevated concentrations of circulating CXCL12α in PAH predicted poorer survival. Furthermore, elevated circulating CXCL12α was an independent risk factor for death that could potentially be included in a prognostic model and guide therapy.

Stenting the stent.

BACKGROUND: Stents are constructed with predefined radial strength which, on occasion, may be insufficient to support a resistant lesion. METHODS: We prospectively assessed the need for, and safety of, implanting a second stent within the first, during the index procedure, in a consecutive series of 500 patients undergoing percutaneous coronary intervention (PCI) by a single operator in the period 1998 2001. The indication was a lesion that appeared angiographically suboptimal after full balloon/stent expansion to high pressure with appropriate sizing. Visible thrombus was an exclusion. Stents were slotted tubes or ring designs whenever possible. Clinical follow-up was > 1 year and angiographic re-study was performed when indicated. RESULTS: We identified 18 patients/lesions (3.6%) that required implantation of a stent within a stent. The appearance was due to tissue/stent prolapse in 72%, edge dissection in 17%, narrow stent inflow/outflow in 5.5% and inadvertent stent detachment in 5.5%. There were no lesion-related acute or in-hospital complications. There was no late thrombosis or death. Follow-up was 21 10 months, and revealed 11% target lesion revascularization, of which half were at the site of stent overlap. CONCLUSION: Stenting the stent, where extra support is required, is safe and effective.

Type I collagen degradation during tissue repair: comparison of mechanisms following fracture and acute coronary syndromes.

There is turnover of type I collagen during tissue repair. The degradation of type I collagen by matrix metalloproteinases (MMPs) is reflected by serum ICTP and that by cathepsins by CTX-I. There is evidence for increases in ICTP after acute coronary syndromes (ACS) and in CTX-I during fracture repair. The involvement of the MMP pathway in fracture repair and cathepsins after myocardial infarction is unclear. We studied 74 men; 22 were admitted to the hospital on the day of their ACS (ST or non-ST elevation myocardial infarction) (mean age 56 years, range 39 to 82) and 9 attended hospital on the day of their tibial shaft fracture (mean age 33 years, range 21 to 79); we had 43 age-matched controls (mean age 54 years, range 20 to 82). Subjects with ACS and tibial shaft fracture were followed up for up to one year; control subjects were used to establish a reference interval. We measured serum ICTP by ELISA (reference interval 1.1 to 17.6 ng/mL) and CTX-I by chemiluminescence (reference interval 0.094 to 0.991 ng/mL). After ACS, the mean ICTP increased from 5.41 to 6.60 ng/mL within one day of admission (p<0.05); the mean CTX-I increased from 0.263 to 0.414 ng/mL (p<0.05). In two cases, the CTX increased to above the reference interval. After tibial shaft fracture, the mean ICTP increased from 5.51 to maximum of 8.71 ng/mL within 28 days of admission (p<0.01); the mean CTX increased from 0.200 to 0.374 ng/mL (p<0.001). In four cases, the CTX increased to above the reference interval. We conclude that the MMP and cathepsin pathways are both implicated in tissue repair in the bone and heart. This may have clinical implications; drugs that block either pathway (TIMPs, cathepsin K inhibitors) may affect the repair of both tissues.

Virtual fractional flow reserve from coronary angiography: modeling the significance of coronary lesions: results from the VIRTU-1 (VIRTUal Fractional Flow Reserve From Coronary Angiography) study.

OBJECTIVES: The aim of this study was to develop a computer model that accurately predicts myocardial fractional flow reserve (FFR) from angiographic images alone, in patients with coronary artery disease. BACKGROUND: Percutaneous coronary intervention (PCI) guided by FFR is superior to standard assessment alone. FFR-guided PCI results in improved clinical outcomes, a reduction in the number of stents implanted, and reduced cost. Currently FFR is used in few patients. A less invasive FFR would be a valuable tool. METHODS: Nineteen patients with stable coronary artery disease awaiting elective PCI were studied. They underwent rotational coronary angiography. The FFR was measured, physiologically significant lesions were stented, and angiography and FFR were repeated. Three-dimensional arterial anatomy pre- and post-stenting was reconstructed offline. Generic boundary conditions for computational fluid dynamics analysis were applied. The virtual fractional flow reserve (vFFR) and measured fractional flow reserve (mFFR) values were compared. RESULTS: Thirty-five matched anatomical and physiological datasets were obtained: 10 right coronary arteries (RCA) (5 pre- and post-stenting), and 12 left coronary arteries (LCA) (8 pre- and post-stenting). The computational fluid dynamics model predicted which lesions were physiologically significant (FFR <0.80) and which were not (FFR >0.80) with accuracy, sensitivity, specificity, positive and negative predictive values of 97%, 86%, 100%, 100%, and 97% respectively. On average, the vFFR values deviated from mFFR by ±0.06 (mean delta = 0.02, SD = 0.08). The vFFR and mFFR were closely correlated (r = 0.84). CONCLUSIONS: We have developed a model of intracoronary physiology based upon a rotational coronary angiogram. Significant lesions were identified with 97% accuracy. The FFR was reliably predicted without the need for invasive measurements or inducing hyperemia.