Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab.

BACKGROUND: Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. METHODS: STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. RESULTS: Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively). CONCLUSIONS: Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients. TRIAL REGISTRATION NUMBER: NCT03004703.

Associations between circulating microRNAs and lipid-rich coronary plaques measured with near-infrared spectroscopy.

Lipid-rich coronary atherosclerotic plaques often cause myocardial infarction (MI), and circulating biomarkers that reflect lipid content may predict risk of MI. We investigated the association between circulating microRNAs (miRs) are lipid-rich coronary plaques in 47 statin-treated patients (44 males) with stable coronary artery disease undergoing percutaneous coronary intervention. We assessed lipid content in non-culprit coronary artery lesions with near-infrared spectroscopy and selected the 4 mm segment with the highest measured lipid core burden index (maxLCBI4mm). Lipid-rich plaques were predefined as a lesion with maxLCBI4mm ≥ 324.7. We analyzed 177 circulating miRs with quantitative polymerase chain reaction in plasma samples. The associations between miRs and lipid-rich plaques were analyzed with elastic net. miR-133b was the miR most strongly associated with lipid-rich coronary plaques, with an estimated 18% increase in odds of lipid-rich plaques per unit increase in miR-133b. Assessing the uncertainty by bootstrapping, miR-133b was present in 82.6% of the resampled dataset. Inclusion of established cardiovascular risk factors did not attenuate the association. No evidence was found for an association between the other analyzed miRs and lipid-rich coronary plaques. Even though the evidence for an association was modest, miR-133b could be a potential biomarker of vulnerable coronary plaques and risk of future MI. However, the prognostic value and clinical relevance of miR-133b needs to be assessed in larger cohorts.

The association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques assessed by near-infrared spectroscopy.

Background: Lipid content in coronary atheromatous plaques, measured by near-infrared spectroscopy (NIRS), can predict the risk of future coronary events. Biomarkers that reflect lipid content in coronary plaques may therefore improve coronary artery disease (CAD) risk assessment. Purpose: We aimed to investigate the association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques in statin-treated patients with stable CAD undergoing percutaneous coronary intervention. Methods: 56 patients with stable CAD underwent three-vessel imaging with NIRS when feasible. The coronary artery segment with the highest lipid content, defined as the maximum lipid core burden index within any 4 mm length across the entire lesion (maxLCBI4mm), was defined as target segment. Lipoprotein subfractions and Lipoprotein a (Lp(a)) were analyzed in fasting serum samples by nuclear magnetic resonance spectroscopy and by standard in-hospital procedures, respectively. Penalized linear regression analyses were used to identify the best predictors of maxLCBI4mm. The uncertainty of the lasso estimates was assessed as the percentage presence of a variable in resampled datasets by bootstrapping. Results: Only modest evidence was found for an association between lipoprotein subfractions and maxLCBI4mm. The lipoprotein subfractions with strongest potential as predictors according to the percentage presence in resampled datasets were Lp(a) (78.1 % presence) and free cholesterol in the smallest high-density lipoprotein (HDL) subfractions (74.3 % presence). When including established cardiovascular disease (CVD) risk factors in the regression model, none of the lipoprotein subfractions were considered potential predictors of maxLCBI4mm. Conclusion: In this study, serum levels of Lp(a) and free cholesterol in the smallest HDL subfractions showed the strongest potential as predictors for lipid content in coronary atheromatous plaques. Although the evidence is modest, our study suggests that measurement of lipoprotein subfractions may provide additional information with respect to coronary plaque composition compared to traditional lipid measurements, but not in addition to established risk factors. Further and larger studies are needed to assess the potential of circulating lipoprotein subfractions as meaningful biomarkers both for lipid content in coronary atheromatous plaques and as CVD risk markers.

Implementing screening for myocardial injury in non-cardiac surgery: perspectives of an ad-hoc interdisciplinary expert group.

Objectives. Perioperative myocardial injury (PMI) is increasingly recognised as an important complication of non-cardiac surgery, with often clinically silent presentation, but detrimental prognosis. Active screening for PMI, involving the detection of dynamic and elevated levels of cardiac troponin, has recently been advocated by an increasing number of guidelines; however, active PMI screening has not been reflected in clinical practice. Design. As consensus on a common screening and management pathway is lacking, we synthesise the current evidence to provide suggestions on the selection of patients for screening, organisation of a screening program, and a potential management pathway, building upon a recently published perioperative screening algorithm. Results. Screening should be performed using high-sensitivity assays both preoperatively and postoperatively (postoperative Days 1 and 2) in patients at high-risk of experiencing perioperative complications. Conclusion. This expert opinion piece by an interdisciplinary group of predominantly Norwegian clinicians aims to assist healthcare professionals planning to implement guideline-recommended PMI screening at a local level in order to improve patient outcomes following non-cardiac surgery.

Coronary Artery Lesion Lipid Content and Plaque Burden in Diabetic and Nondiabetic Patients: PROSPECT II.

BACKGROUND: Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid content. METHODS: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion-related MACEs and high-risk plaque characteristics. RESULTS: Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% [odds ratio (OR), 1.94 (95% CI, 1.14-3.30)]), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% [OR, 3.78 (95% CI, 1.12-12.77)]) and nonculprit lesion-related spontaneous myocardial infarction (9.3% versus 3.8% [OR, 2.74 (95% CI, 1.25-6.04)]). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%, P=0.34; maximum lipid core burden index ≥324.7: 66% versus 70%, P=0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%, P=0.37; maximum lipid core burden index ≥324.7: 26% versus 24%, P=0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 [95% CI, 1.21-5.04]) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 [95% CI, 0.86-1.69]). CONCLUSIONS: Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02171065.

High-intensity interval training induces beneficial effects on coronary atheromatous plaques: a randomized trial.

AIMS: Coronary atheroma volume is associated with risk of coronary events in coronary artery disease (CAD). Exercise training is a cornerstone in primary and secondary prevention of CAD, but the effect of exercise on coronary atheromatous plaques is largely unknown. We assessed the effect of 6 months supervised high-intensity interval training (HIIT) on coronary plaque geometry using intravascular ultrasound in patients with stable CAD following percutaneous coronary intervention (PCI). METHODS AND RESULTS: Sixty patients were randomized to two sessions of weekly supervised HIIT at 85-95% of peak heart rate (n = 30) or to follow contemporary preventive guidelines (control group, n = 30). The study endpoints were change in percent atheroma volume (PAV) and total atheroma volume (TAV) normalized for segment length (TAVnorm) at 6-month follow-up. The change in average PAV for matched coronary segments from baseline to follow-up showed a significant between-group difference (-1.4, 95% CI: -2.7 to -0.1, P = 0.036). There was a significant reduction in the HIIT group (-1.2, 95% CI: -2.1 to -0.2, P = 0.017) while not in the control group (0.2, 95% CI: -0.7 to 1.1, P = 0.616). TAVnorm was reduced (-9 mm3, 95% CI: -14.7 to -3.4, P = 0.002) after HIIT, with a significant between-group difference (-12.0 mm3, 95% CI: -19.9 to -4.2, P = 0.003). CONCLUSION: In patients with established CAD, a regression of atheroma volume was observed in those undergoing 6 months of supervised HIIT compared with patients following contemporary preventive guidelines. Our study indicates that HIIT counteracts atherosclerotic coronary disease progression and reduces atheroma volume in residual coronary atheromatous plaques following PCI.

Small LDL subfractions are associated with coronary atherosclerosis despite no differences in conventional lipids.

Lipoprotein subfractions currently represent a new source of cardiovascular disease (CVD) risk markers that may provide more information than conventional lipid measures. We aimed to investigate whether lipoprotein subfractions are associated with coronary atherosclerosis in patients without prior known CVD. Fasting serum samples from 60 patients with suspected coronary artery disease (CAD) were collected before coronary angiography and analyzed by nuclear magnetic resonance (NMR) spectroscopy. The severity of coronary atherosclerosis was quantified by the Gensini score (≤20.5 = nonsignificant coronary atherosclerosis, 20.6-30.0 = intermediate coronary atherosclerosis, ≥30.1 = significant CAD). Differences in lipoprotein subfractions between the three Gensini groups were assessed by two-way ANOVA, adjusted for statin use. Despite no differences in conventional lipid measures between the three Gensini groups, patients with significant CAD had higher apolipoprotein-B/apolipoprotein-A1 ratio, 30% more small and dense low-density lipoprotein 5 (LDL-5) particles, and increased levels of cholesterol, triglycerides, and phospholipids within LDL-5 compared with patients with nonsignificant coronary atherosclerosis and intermediate coronary atherosclerosis (P ≤ 0.001). In addition, the low-density lipoprotein (LDL) cholesterol/high-density lipoprotein cholesterol ratio, and triglyceride levels of LDL 4 were significantly increased in patients with significant CAD compared with patients with nonsignificant coronary atherosclerosis. In conclusion, small and dense lipoprotein subfractions were associated with coronary atherosclerosis in patients without prior CVD. Additional studies are needed to explore whether lipoprotein subfractions may represent biomarkers offering a clinically meaningful improvement in the risk prediction of CAD.

CENIT (Impact of Cardiac Exercise Training on Lipid Content in Coronary Atheromatous Plaques Evaluated by Near-Infrared Spectroscopy): A Randomized Trial.

Background The effect of physical exercise on lipid content of coronary artery plaques is unknown. With near infrared spectroscopy we measured the effect of high intensity interval training (HIIT) on lipid content in coronary plaques in patients with stable coronary artery disease following percutaneous coronary intervention. Methods and Results In CENIT (Impact of Cardiac Exercise Training on Lipid Content in Coronary Atheromatous Plaques Evaluated by Near-Infrared Spectroscopy) 60 patients were randomized to 6 months supervised HIIT or to a control group. The primary end point was change in lipid content measured as maximum lipid core burden index at 4 mm (maxLCBI4mm). A predefined cutoff of maxLCBI4mm >100 was required for inclusion in the analysis. Forty-nine patients (HIIT=20, usual care=29) had maxLCBI4mm >100 at baseline. Change in maxLCBI4mm did not differ between groups (-1.2, 95% CI, -65.8 to 63.4, P=0.97). The estimated reduction in maxLCBI4mm was -47.7 (95% CI, -100.3 to 5.0, P=0.075) and -46.5 (95% CI, -87.5 to -5.4, P=0.027) after HIIT and in controls, respectively. A negative correlation was observed between change in peak oxygen uptake (VO2peak) and change in lipid content (Spearman's correlation -0.44, P=0.009). With an increase in VO2peak above 1 metabolic equivalent task, maxLCBI4mm was on average reduced by 142 (-8 to -262), whereas the change was -3.2 (154 to -255) with increased VO2peak below 1 metabolic equivalent task. Conclusions Six months of HIIT following percutaneous coronary intervention did not reduce lipid content in coronary plaques compared with usual care. A moderate negative correlation between increase in VO2peak and change in lipid content generates the hypothesis that exercise with a subsequent increase in fitness may reduce lipid content in coronary atheromatous plaques. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02494947.

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

BACKGROUND: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. METHODS: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). FINDINGS: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. INTERPRETATION: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. FUNDING: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

Associations between circulating microRNAs and coronary plaque characteristics: potential impact from physical exercise.

microRNAs (miRs) are involved in different steps in the development of atherosclerosis and are proposed as promising biomarkers of coronary artery disease (CAD). We hypothesized that circulating levels of miRs were associated with coronary plaque components assessed by radiofrequency intravascular ultrasound (RF-IVUS) before and after aerobic exercise intervention. Thirty-one patients with CAD treated with percutaneous coronary intervention (PCI) previously included in a randomized trial with aerobic interval training (AIT) or moderate continuous training (MCT) as post-PCI intervention were included. Coronary plaque characteristics by grayscale and RF-IVUS and predefined circulating candidate miRs in plasma were analyzed at baseline and follow-up. Associations between miRs and coronary plaque composition, and the potential effect from exercise, were analyzed using linear regression. Circulating levels of miR-15a-5p, miR-30e-5p, miR-92a-3p, miR-199a-3p, miR-221-3p, and miR-222-3p were associated with baseline coronary necrotic core volume. Following exercise intervention, decreased levels of miR-15a-5p, miR-93-5p, and miR-451a, and increased levels of miR-146a-5p were associated with an observed regression of coronary plaque burden. A mirPath prediction tool identified that genes regulated by miR-15a-5p, miR-199a-3p, and miR-30e-5p were significantly overrepresented in pathways related to fatty acid biosynthesis and fatty acid metabolism. This exploratory study demonstrated six miRs associated with coronary necrotic core, a marker of plaque vulnerability. In addition, changes in four miRs were associated with a regression of coronary plaque burden following exercise intervention. These novel findings may identify potential future biomarkers of CAD and coronary plaque composition.

Drug-Eluting versus Bare-Metal Stents in Saphenous Vein Grafts Compared to Native Coronary Vessels: The Norwegian Coronary Stent Trial Study.

BACKGROUND: Drug-eluting stents (DES) reduce target lesion revascularization (TLR) with no effect on mortality or myocardial infarction (MI) compared to bare-metal stents (BMS) in native vessels. Randomized stent studies in saphenous vein grafts (SVG) are few and the reported effects are ambiguous. The Norwegian Coronary Stent Trial study is the first to randomize lesions to percutaneous coronary intervention in native vessels and SVG. AIMS: The aim of this study was to compare the rate of mortality, MI, and TLR across stent and vessel types. METHODS: In this substudy, 6,087 patients with a single lesion in native vessels and 164 in SVG were followed for 5 years. RESULTS: MI was more frequent in SVG (subdistributional hazard ratio [SHR] 4.95 (3.75-6.54, p < 0.001), but not affected by stent type. In the first 500 days, DES reduced TLR in native vessels (SHR 0.21 (0.15-0.30) p < 0.001) and SVG (SHR 0.18 (0.04-0.80) p = 0.02). Thereafter, DES and BMS were equivalent in native vessels, but DES had a higher TLR rate than BMS in SVG (SHR 3.31 (1.23-8.94) p = 0.02). After 5 years, the TLR rate was still significantly lower for DES in native vessels (3.2% vs. 7.8%, p < 0.001) but not in SVG (21.4% vs. 18. 4%). CONCLUSION: In SVG, no difference in TLR between DES and BMS was observed after 5 years in contrast to persistent benefit in native vessels. The high rate of TLR and MI in SVG makes treatment of native vessels a preference whenever feasible and better treatment options for SVG are warranted.

REBOARREST, resuscitative endovascular balloon occlusion of the aorta in non-traumatic out-of-hospital cardiac arrest: a study protocol for a randomised, parallel group, clinical multicentre trial.

BACKGROUND: Survival after out-of-hospital cardiac arrest (OHCA) is poor and dependent on high-quality cardiopulmonary resuscitation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be advantageous in non-traumatic OHCA due to the potential benefit of redistributing the cardiac output to organs proximal to the aortic occlusion. This theory is supported by data from both preclinical studies and human case reports. METHODS: This multicentre trial will enrol 200 adult patients, who will be randomised in a 1:1 ratio to either a control group that receives advanced cardiovascular life support (ACLS) or an intervention group that receives ACLS and REBOA. The primary endpoint will be the proportion of patients who achieve return of spontaneous circulation with a duration of at least 20 min. The secondary objectives of this trial are to measure the proportion of patients surviving to 30 days with good neurological status, to describe the haemodynamic physiology of aortic occlusion during ACLS, and to document adverse events. DISCUSSION: Results from this study will assess the efficacy and safety of REBOA as an adjunctive treatment for non-traumatic OHCA. This novel use of REBOA may contribute to improve treatment for this patient cohort. TRIAL REGISTRATION: The trial is approved by the Regional Committee for Medical and Health Research Ethics in Norway (reference 152504) and is registered at ClinicalTrials.gov (reference NCT04596514) and as Universal Trial Number WHO: U1111-1253-0322.

Tocilizumab increases citrullinated histone 3 in non-ST segment elevation myocardial infarction.

OBJECTIVE: Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties. METHODS: In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase-DNA (MPO-DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1-3). RESULTS: Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p<0.05), and H3Cit area under the curve (AUC) was 2.3 fold higher in the tocilizumab compared with placebo group (p<0.0001). (2) MPO-DNA and dsDNA did not differ between the groups. (3) In both treatment arms, dsDNA AUC was associated with TnT AUC. (4) Neutrophil count AUC correlated inversely to H3Cit AUC (p=0.015) in the total population. CONCLUSIONS: In patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

Analyses of Increased Mortality in New and Known Diabetes in Patients with Coronary Disease Enrolled in the NORSTENT Randomized Study.

BACKGROUND: NORSTENT trial randomized 9,013 patients to percutaneous coronary intervention with drug-eluting stents (DES) or bare-metal stents (BMS) with a 5-year follow-up. Among the patients, 5,512 had measured either fasting glucose level or percent glycated hemoglobin (HbA1c) at the index procedure. That cohort constitutes the present study population analyzing mortality and evaluating treatment heterogeneity of randomized stent in diabetic versus nondiabetic subgroups. RESULTS: The cohort consisted of 4,174 (75.7%) patients without diabetes, 716 (13.0%) with known diabetes, and 622 (11.3%) with no diabetes in history but elevated fasting glucose level >7.0 mmol/L or HbA1c >6.5% and therefore defined as new diabetes. Patients with known diabetes had a significantly increased all-cause (hazard ratio [HR] 1.99, 95% CI 1.51-2.62, p < 0.001), cardiac (subhazard ratio [SHR] 2.47, 95% CI 1.55-3.93, p < 0.001), and noncardiac (SHR 1.74, 95% CI 1.23-2.44, p = 0.002) mortality after adjustment for baseline variables. In the follow-up of 5 years, patients with new diabetes, however, had a marginally increased all-cause (HR 1.40, 95% CI 1.01-1.93, p = 0.043) and significantly increased noncardiac mortality (SHR 1.52, 95% CI 1.06-2.20, p = 0.025), but no increase in cardiac mortality (SHR 1.06, 95% CI 0.53-2.12, p = 0.86) after the same adjustment. The majority of the mortality was cardiac in the first 1-2 years after intervention; thereafter, noncardiac mortality dominated. However, the time period for when noncardiac mortality became the dominating cause varied considerably and significantly between the groups. There was no heterogeneity in mortality in response to randomized stent between diabetics and nondiabetics. CONCLUSION: Known diabetes has increased cardiac and noncardiac mortality in contrast to new diabetes which is only associated with increased noncardiac mortality during the 5-year follow-up. Diabetic and nondiabetic patients have the same response to the treatment with BMS or DES.

Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study.

BACKGROUND: Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs). METHODS: PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065. FINDINGS: Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55-70] years). Median follow-up was 3·7 (IQR 3·0-4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0-15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2-10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25-4·13) and non-culprit lesion-specific MACEs (7·83, 4·12-14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0-10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4-17·6). INTERPRETATION: Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes. FUNDING: Abbott Vascular, Infraredx, and The Medicines Company.

Impact of baseline coronary flow and its distribution on fractional flow reserve prediction.

Model-based prediction of fractional flow reserve (FFR) in the context of stable coronary artery disease (CAD) diagnosis requires a number of modelling assumptions. One of these assumptions is the definition of a baseline coronary flow, ie, total coronary flow at rest prior to the administration of drugs needed to perform invasive measurements. Here we explore the impact of several methods available in the literature to estimate and distribute baseline coronary flow on FFR predictions obtained with a reduced-order model. We consider 63 patients with suspected stable CAD, for a total of 105 invasive FFR measurements. First, we improve a reduced-order model with respect to previous results and validate its performance versus results obtained with a 3D model. Next, we assess the impact of a wide range of methods to impose and distribute baseline coronary flow on FFR prediction, which proved to have a significant impact on diagnostic performance. However, none of the proposed methods resulted in a significant improvement of prediction error standard deviation. Finally, we show that intrinsic uncertainties related to stenosis geometry and the effect of hyperemic inducing drugs have to be addressed in order to improve FFR prediction accuracy.

Stent edge vascular response and in-stent geometry after aerobic exercise.

The purpose of the present study was to investigate the edge vascular response in patients treated with second-generation drug-eluting stents (DES) after 3 months of aerobic exercise intervention. Thirty-two patients with significant coronary artery disease underwent percutaneous coronary intervention with DES implantation prior to randomization to aerobic interval training (AIT, 14 patients) versus moderate continuous training (MCT, 18 patients). Plaque changes were assessed using grayscale and radiofrequency intravascular ultrasound at baseline and follow-up. The main endpoints were changes in plaque burden and necrotic core content in the 5-mm proximal and distal stent edges. Plaque burden in the distal stent edges decreased significantly in both groups (AIT: - 3.3%; MCT: - 0.4%, p = 0.01 for both), and more in the AIT group (p = 0.048). Necrotic core content decreased significantly in the distal stent edges in both groups (- 2.1 mm3 in AIT, - 0.3 mm3 in MCT, p = 0.01 for both), and more in the AIT group (p = 0.03). There were no significant changes in proximal stent edges or in in-stent geometry at follow-up. In this small study of patients treated with DES implantation, 3 months of aerobic exercise training demonstrated decreased plaque burden and necrotic core content in the distal stent edges, with larger reductions in the AIT group.

Polymer-free drug-coated vs. bare-metal coronary stents in patients undergoing non-cardiac surgery: a subgroup analysis of the LEADERS FREE trial.

AIMS: To compare the outcomes of patients undergoing non-cardiac surgery (NCS) after PCI with either a drug-coated stent (DCS) or a bare-metal stent (BMS), followed by 1-month dual antiplatelet therapy and to explore the impact of the timing of NCS. METHODS: This is a subgroup analysis of the LEADERS FREE trial. The primary safety end point was a composite of cardiac death, myocardial infarction, or stent thrombosis, and the primary efficacy end point was clinically driven target lesion revascularization (TLR). RESULTS: Out of 2432 patients included in the LEADERS FREE trial, 278 (11.4%) underwent NCS within 1 year after PCI. Among NCS patients, the 1-year safety end point was numerically lower with DCS; however, this difference was not significant as compared to BMS (4.7% vs. 10.1%, HR: 0.459 [0.178-1.183], p = 0.099), clinically driven TLR was significantly lower after DCS (2.4% vs. 8.3%, HR: 0.281 [0.079-0.996], p = 0.036), and BARC 3-5 bleeding was similar with DCS vs. BMS (10.2% vs. 7.5%, p = 0.438). In patients treated with BMS, NCS within 3 months after PCI was associated with higher incidence of the safety end point than NCSs performed later: 14.9% vs. 4.4%, HR: 3.586 [1.012-12.709], p = 0.034. The timing of surgery had no impact on patients treated with DCS (4.7% vs. 4.7%, p = 0.947). CONCLUSIONS: Among patients undergoing NCS after PCI, DCS-treated patients had a lower probability of clinically driven TLR compared with BMS. However, there was no significant difference in the occurrence of the primary composite safety end point or bleeding complications. Early NCS after BMS-PCI was associated with impaired safety, while the timing of NCS had no such influence after DCS implantation.