Espen Holte

Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial

AIMS Interleukin-6 (IL-6) contributes to atherosclerotic plaque destabilization and is involved in myocardial injury during ischaemia-reperfusion. Interleukin-6 is therefore a potential therapeutic target in myocardial infarction (MI). We hypothesized that the IL-6 receptor antagonist tocilizumab would attenuate inflammation, and secondarily reduce troponin T (TnT) release in non-ST-elevation MI (NSTEMI). METHODS AND RESULTS In a two-centre, double-blind, placebo-controlled trial, 117 patients with NSTEMI were randomized at a median of 2 days after symptom onset to receive placebo (n = 59) or tocilizumab (n = 58), administered as a single dose prior to coronary angiography. High sensitivity (hs) C-reactive protein and hsTnT were measured at seven consecutive timepoints between Days 1 and 3. The area under the curve (AUC) for high-sensitivity C-reactive protein was the primary endpoint. The median AUC for high-sensitivity C-reactive protein during hospitalization was 2.1 times higher in the placebo than in the tocilizumab group (4.2 vs. 2.0 mg/L/h, P < 0.001). Also, the median AUC for hsTnT during hospitalization was 1.5 times higher in the placebo group compared with the tocilizumab group (234 vs. 159 ng/L/h, P = 0.007). The differences between the two treatment groups were observed mainly in (i) patients included ≤2 days from symptom onset and (ii) patients treated with percutaneous coronary intervention (PCI). No safety issues in the tocilizumab group were detected during 6 months of follow-up. CONCLUSION Tocilizumab attenuated the inflammatory response and primarily PCI-related TnT release in NSTEMI patients.

Coronary flow velocity reserve in the three main coronary arteries assessed with transthoracic Doppler: a comparative study with quantitative coronary angiography.

BACKGROUND The purpose of this study was to evaluate the potential of combined use of transthoracic Doppler echocardiographic coronary flow velocity reserve (CFVR) measurements and findings of retrograde coronary flow in the three main coronary arteries for the assessment of borderline (angiographic diameter stenosis, 50%-75%) and high-grade (angiographic diameter stenosis, 76%-100%) coronary artery stenoses. METHODS A total of 108 patients scheduled for coronary angiography because of chest pain or acute coronary syndromes were studied. CFVR was measured during adenosine-induced hyperemia in the mid to distal segments of the left anterior descending coronary artery, the marginal branches of the left circumflex coronary artery, and the posterior descending coronary artery, with peak CFVR (pCFVR) <2.0 implying hemodynamic significant stenosis. CFVR results were compared with results from quantitative coronary angiography, with stenosis severity in the left main and three major coronary arteries divided into three groups: (1) diameter stenosis 0% to 49%, (2) diameter stenosis 50% to 75%, and (3) diameter stenosis 76% to 100%. RESULTS In patients with antegrade flow in the relevant coronary artery segment, CFVR was successfully measured in the mid to distal left anterior descending artery, the marginal branches of the left circumflex artery, and the posterior descending artery in 97%, 63%, and 75% of patients, respectively. CFVR was significantly different among the stenosis groups, with pCFVR of 2.79 ± 0.77 in group 1, 2.01 ± 0.72 in group 2, and 1.50 ± 0.69 in group 3 (P < .001 among groups). Angiography confirmed retrograde flow in seven of the nine arteries found by transthoracic echocardiography. Findings of pCFVR <2.0 or retrograde coronary artery flow correctly identified 42 of 49 patients with stenoses in group 3, with sensitivity, specificity, and positive and negative predictive values of 86%, 70%, 70%, and 85%, respectively. In group 2, pCFVR values were widely distributed above or below the defined pCFVR cutoff value. CONCLUSIONS CFVR measurement in the mid to distal left anterior descending artery was feasible in almost all patients, and in the marginal branches of the left circumflex artery and the posterior descending artery in two thirds and three quarters of patients, respectively. Use of the combined echocardiographic criteria had high precision for diagnosing severe coronary stenoses (diameter stenosis, 76%-100%). The functional significance of angiographically borderline stenoses (diameter stenosis, 50%-75%) may be further differentiated by the use of CFVR measurements.

Heart Failure and Asymptomatic Left Ventricular Systolic Dysfunction in Lymphoma Survivors Treated With Autologous Stem-Cell Transplantation: A National Cross-Sectional Study

PURPOSE We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD), including symptomatic (ie, heart failure [HF]) and asymptomatic LVSD in adult lymphoma survivors (LSs) after autologous hematopoietic stem-cell transplantation (auto-HCT) and to identify risk factors for LVSD in this population. PATIENTS AND METHODS All LSs treated with auto-HCT as adults in Norway from 1987 to 2008 were eligible for this national cross-sectional study. Asymptomatic LVSD was defined as left ventricular ejection fraction less than 50% by echocardiography, and HF was defined according to current recommendations. The results in LSs were compared with those found in an age- and sex-matched (1:1) control group. RESULTS We examined 274 LSs (69% of all eligible survivors); 62% were men, the mean (± standard deviation) age was 56 ± 12 years, and mean follow-up time from lymphoma diagnosis was 13 ± 6 years. The mean cumulative doxorubicin dose was 316 ± 111 mg/m(2), and 35% of LSs had received additional radiation therapy involving the heart. We found LVSD in 15.7% of the LSs, of whom 5.1% were asymptomatic. HF patients were symptomatically mildly affected, with 8.8% of all LSs classified as New York Heart Association class II, whereas more severe HF was rare (1.8%). Compared with controls, LSs had a substantially increased LVSD risk (odds ratio, 6.6; 95% CI, 2.5 to 17.6; P < .001). A doxorubicin dose ≥ 300 mg/m(2) and cardiac radiation therapy dose greater than 30 Gy were independent risk factors for LVSD. CONCLUSION LVSD was frequent and HF more prevalent than previously reported in LSs after auto-HCT. Our results may help to identify LSs at increased LVSD risk and can serve as a basis for targeted surveillance strategies.

Transthoracic echocardiography for imaging of the different coronary artery segments: a feasibility study

BackgroundTransthoracic echocardiography (TTE) may be used for direct inspection of various parts of the main coronary arteries for detection of coronary stenoses and occlusions. We aimed to assess the feasibility of TTE to visualise the complete segments of the left main (LM), left descending (LAD), circumflex (Cx) and right (RCA) coronary arteries.MethodsOne hundred and eleven patients scheduled for diagnostic coronary angiography because of chest pain or acute coronary syndrome had a TTE study to map the passage of the main coronary arteries. LAD, Cx and RCA were each divided into proximal, middle and distal segments. If any part of the individual segment of a coronary artery with antegrade blood flow was not visualised, the segment was labeled as not satisfactorily seen.ResultsComplete imaging of the LM was achieved in 98% of the patients. With antegrade directed coronary artery flow, the proximal, middle and distal segments of LAD were completely seen in 96%, 95% and 91% of patients, respectively. Adding the completely seen segments with antegrade coronary flow and segments with retrograde coronary flow, the proximal, middle and distal segments of LAD were adequately visualised in 96%, 96% and 93% of patients, respectively. With antegrade directed coronary artery flow, the proximal, middle and distal segments of Cx were completely seen in 88%, 61% and 3% and in RCA in 40%, 28% and 54% of patients. Retrograde coronary artery flow was correctly identified as verified by coronary angiography in seven coronary segments, mainly in the posterior descending artery (labeled as the distal segment of RCA) and distal LAD.ConclusionsTTE is a feasible method for complete demonstration of coronary flow in the LM, the proximal Cx and the different segments of LAD, but less suitable for the RCA and mid and distal segments of the Cx. (ClinicalTrials.gov number NTC00281346.)

Valvular Dysfunction in Lymphoma Survivors Treated with Autologous Stem Cell Transplantation A National Cross-Sectional Study

OBJECTIVES This study assessed the prevalence and associated risk factors for valvular dysfunction (VD) observed in adult lymphoma survivors (LS) after autologous hematopoietic stem cell transplantation (auto-HCT), and to determine whether anthracycline-containing chemotherapy (ACCT) alone in these patients is associated with VD. BACKGROUND The prevalence of and risk factors for VD in LS after auto-HCT is unknown. Anthracyclines may induce heart failure, but any association with VD is not well-defined. METHODS This national cross-sectional study included all adult LS receiving auto-HCT from 1987 to 2008 in Norway. VD was defined by echocardiography as either more than mild regurgitation or any stenosis. Observations in LS were compared with a healthy age- and gender-matched (1:1) control group. RESULTS In total, 274 LS (69% of all eligible) participated. Mean age was 56 ± 12 years, mean follow-up time after lymphoma diagnosis was 13 ± 6 years, and 62% of participants were males. Mean cumulative anthracycline dosage was 316 ± 111 mg/m(2), and 35% had received radiation therapy involving the heart (cardiac-RT). VD was observed in 22.3% of the LS. Severe VD was rare (n = 9; 3.3% of all LS) and mainly aortic stenosis (n = 7). We observed VD in 16.7% of LS treated with ACCT alone (n = 177), corresponding with a 3-fold increased VD risk (odds ratio: 2.9; 95% confidence interval: 1.5 to 5.8; p = 0.002) compared with controls. Furthermore, the presence of aortic valve degeneration was increased in the LS after ACCT alone compared with controls (13.0% vs. 2.9%; p < 0.001). Female sex, age >50 years at lymphoma diagnosis, ≥3 lines of chemotherapy before auto-HCT, and cardiac-RT >30 Gy were identified as independent risk factors for VD in the LS. CONCLUSIONS In LS, ACCT alone was significantly associated with VD and related to valvular degeneration. Overall, predominantly moderate VD was prevalent in LS, and longer observation time is needed to clarify the clinical significance of this finding.

Effect of interleukin-6 inhibition on coronary microvascular and endothelial function in myocardial infarction

Objective Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI). Methods This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months. Results Tocilizumab did not affect CFR during hospitalisation (tocilizumab: 3.4±0.8 vs placebo: 3.3±1.2, p=0.80). CFR improved significantly in both groups at 6 months. Patients in the tocilizumab group had significantly higher area under the curve for VCAM-1 (median 622 vs 609 ng/mL/hour, tocilizumab and placebo respectively, p=0.003). There were inverse correlations between VCAM-1 and CFR in the placebo (hospitalisation: r=−0.74, p<0.01, 6 months: r=−0.59, p<0.01), but not in the tocilizumab group (hospitalisation: r=0.20, p=0.37, 6 months r=−0.28, p=0.20). Conclusions Tocilizumab did not affect CFR during hospitalisation or after 6 months. Tocilizumab increased VCAM-1 levels during hospitalisation, but this was not associated with reduced CFR in these patients.

Transthoracic Doppler for detection of stenoses in the three main coronary arteries by use of stenotic to prestenotic velocity ratio and aliased coronary flow

AIMS Our aim was to determine the feasibility and accuracy of diagnosing significant coronary artery stenoses using peak stenotic to prestenotic velocity ratio (pSPVR) measurements when compared with results from quantitative coronary angiography and coronary flow velocity reserve (CFVR) assessed by transthoracic echocardiography (TTE). METHODS AND RESULTS One hundred and eight patients scheduled for coronary angiography were studied using transthoracic Doppler echocardiography. Stenoses were identified by local colour aliasing by colour flow Doppler, and further evaluated by pSPVR, using a pSPVR of ≥2.0 as a cut-off for significant stenosis. When pSPVR could not be measured, local mosaic coronary flow pattern at Nyquist limit ≥0.48 m/s was used. Sixty-five lesions suggestive of stenosis were found by TTE. Combining findings of pSPVR ≥2.0 and local mosaic flow at Nyquist limit ≥0.48 m/s, the sensitivity and specificity of demonstrating significant stenoses (diameter stenosis, 50-99%) in the left main coronary artery (LM), left anterior descending coronary (LAD), left circumflex coronary (Cx), and right coronary artery (RCA) were 75 and 98%, 74 and 95%, 40 and 87%, and 34 and 98%, respectively. The pSPVR did not differ significantly between arteries with reduced and normal CFVR, with a cut-off of CFVR <2.0. CONCLUSIONS Findings of pSPVR ≥2.0 or localized colour flow aliasing are useful in the non-invasive diagnosis of significant coronary disease in the three main coronary arteries, with high specificity for detecting significant stenoses. These findings showed high sensitivity for identifying significant stenoses in the LM and LAD, but showed lower ability to detect those lesions in the Cx and RCA.

Transthoracic Doppler Echocardiography for Detection of Stenoses in the Left Coronary Artery by Use of Poststenotic Coronary Flow Profiles: A Comparison with Quantitative Coronary Angiography and Coronary Flow Reserve

BACKGROUND The aim of this study was to determine whether poststenotic diastolic-to-systolic velocity ratio (DSVR) assessed by transthoracic Doppler echocardiography could accurately identify significant stenoses in the left coronary artery. METHODS A total of 108 patients scheduled for coronary angiography because of chest pain or acute coronary syndromes were studied. RESULTS The success rates of peak DSVR (pDSVR) measurements in the distal to mid left anterior descending coronary artery and marginal branches of the left circumflex coronary artery were 85% and 32%, respectively. With peak coronary flow velocity reserve as a reference, pDSVR was significantly higher in arteries with normal coronary flow reserve (peak coronary flow velocity reserve ≥ 2.0) compared with arteries with reduced coronary flow reserve (peak coronary flow velocity reserve < 2.0) (1.86 ± 0.32 vs 1.53 ± 0.31, P < .0001). In comparison with quantitative coronary angiography, pDSVR was significantly higher in lesions with diameter stenosis < 50% compared with those with diameter stenosis of 50% to 75% (1.92 ± 0.32 vs 1.53 ± 0.18, P < .0001) or diameter stenosis of 76% to 100% (1.43 ± 0.13, P < .0001). Receiver operating characteristic curves showed pDSVR < 1.68 to be the optimal cutoff value for identifying both functionally significant stenoses and diameter stenoses ≥ 50%, with sensitivity of 86% and 90%, specificity of 74% and 84%, positive predictive value of 51% and 71%, and negative predictive value of 94% and 95%, respectively. CONCLUSIONS Transthoracic pDSVR measurements in the distal to mid left anterior descending coronary artery and marginal branches of the left circumflex coronary artery had high accuracy for excluding functionally significant stenoses in the left coronary artery, as well as for identifying angiographic significant stenoses.

Direct visualization of a significant stenosis of the right coronary artery by transthoracic echocardiography. A case report

Non-invasive imaging of coronary arteries by transthoracic echocardiography is an emerging diagnostic tool to study the left main (LM), left descending artery (LAD), circumflex (Cx) and right coronary artery (RCA). Impaired coronary circulation can be assessed by measuring coronary velocity flow reserve (CVFR) by transthoracic Doppler echocardiography. Coronary artery stenoses can be identified as localized colour aliasing and accelerated flow velocities. We report a case with an acute coronary syndrome (ACS) of a 46-year-old man. With non-invasive imaging of coronary arteries by transthoracic echocardiography (TTE), we identified a segment of the mid right coronary artery (RCA) suggestive of stenosis with localized colour aliasing and accelerated flow velocity. We found a high ratio between the stenotic peak velocity and the prestenotic peak velocity, and a pathologic coronary flow velocity reserve (CFVR) distal to the stenosis in the posterior interventricular descending branch (RDP). Subsequent coronary angiography demonstrated one vessel disease with a stenosis in segment 3 of RCA, which was successfully treated with percutaneos coronary intervention PCI. Two weeks following the PCI procedure he was readmitted to hospital with chest pain. A subacute stent thrombosis was questioned, and repeated echocardiography was preformed. The mid portion of RCA showed normal and laminar flow. The CVFR of RCA measured in the RDP showed normal vasodilatory response, confirming an open RCA without any flow limitation. A repeated coronary angiogram demonstrated only a mild in stent intimal hyperplasia. This case illustrates the value of transthoracic echocardiography as a tool both in the diagnosis and the follow-up of chest pain disorders and coronary flow problems. Transthoracic echocardiography allows both direct visualization of the various coronary segments and assessment of the CVFR.

Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1β in non-ST-elevation myocardial infarction

AIM To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI). METHODS 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay. RESULTS Using a mixed between-within subjects analysis of variance, we observed a significant (p < 0.001) between-group difference in changes for interferon gamma-inducible protein (IP-10) and macrophage inflammatory protein-1β (MIP-1β), due to significant increases in the tocilizumab group during hospitalisation (i.e., IP-10 median change from baseline during hospitalisation (mΔ), placebo: 3 (-60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1β mΔ, placebo: 5 (-2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1β was inversely correlated to troponin T (r = -0.28, p < 0.05) and neutrophils (r = -0.32, p < 0.05) in the tocilizumab group. In contrast, tocilizumab had only modest or no effects on the other examined cytokines. CONCLUSIONS Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074.