Efficacy of a web-based intervention for improving psychosocial well-being in patients with implantable cardioverter-defibrillators: the randomized controlled ICD-FORUM trial.

AIMS: Anxiety, depression, and reduced quality of life (QoL) are common in patients with implantable cardioverter-defibrillators (ICDs). Treatment options are limited and insufficiently defined. We evaluated the efficacy of a web-based intervention (WBI) vs. usual care (UC) for improving psychosocial well-being in ICD patients with elevated psychosocial distress. METHODS AND RESULTS: This multicentre, randomized controlled trial (RCT) enrolled 118 ICD patients with increased anxiety or depression [≥6 points on either subscale of the Hospital Anxiety and Depression Scale (HADS)] or reduced QoL [≤16 points on the Satisfaction with Life Scale (SWLS)] from seven German sites (mean age 58.8 ± 11.3 years, 22% women). The primary outcome was a composite assessing change in heart-focused fear, depression, and mental QoL 6 weeks after randomization to WBI or UC, stratified for age, gender, and indication for ICD placement. Web-based intervention consisted of 6 weeks' access to a structured interactive web-based programme (group format) including self-help interventions based on cognitive behaviour therapy, a virtual self-help group, and on-demand support from a trained psychologist. Linear mixed-effects models analyses showed that the primary outcome was similar between groups (ηp2 = 0.001). Web-based intervention was superior to UC in change from pre-intervention to 6 weeks (overprotective support; P = 0.004, ηp2 = 0.036), pre-intervention to 1 year (depression, P = 0.004, ηp2 = 0.032; self-management, P = 0.03, ηp2 = 0.015; overprotective support; P = 0.02, ηp2 = 0.031), and 6 weeks to 1 year (depression, P = 0.02, ηp2 = 0.026; anxiety, P = 0.03, ηp2 = 0.022; mobilization of social support, P = 0.047, ηp2 = 0.018). CONCLUSION: Although the primary outcome was neutral, this is the first RCT showing that WBI can improve psychosocial well-being in ICD patients.

On the role of inelastic scattering in phase-plate transmission electron microscopy.

The phase contrast of Au nanoparticles on amorphous-carbon films with different thicknesses is analyzed using an electrostatic Zach phase plate in a Zeiss 912 Ω transmission electron microscope with in-column energy filter. Specifically, unfiltered and plasmon-filtered phase-plate transmission electron microscopy (PP TEM) images are compared to gain insight in the role of coherence after inelastic scattering processes. A considerable phase-contrast contribution resulting from a combined elastic-inelastic scattering process is found in plasmon-filtered PP TEM images. The contrast reduction compared to unfiltered images mainly originates from zero-order beam broadening caused by the inelastic scattering process. The effect of the sequence of the elastic and inelastic scattering processes is studied by varying the position of the nanoparticles, which can be either located on top or at the bottom of the amorphous-carbon film with respect to the incident electron beam direction.

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

MR-IMPACT II: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial.

AIMS: Perfusion-cardiac magnetic resonance (CMR) has emerged as a potential alternative to single-photon emission computed tomography (SPECT) to assess myocardial ischaemia non-invasively. The goal was to compare the diagnostic performance of perfusion-CMR and SPECT for the detection of coronary artery disease (CAD) using conventional X-ray coronary angiography (CXA) as the reference standard. METHODS AND RESULTS: In this multivendor trial, 533 patients, eligible for CXA or SPECT, were enrolled in 33 centres (USA and Europe) with 515 patients receiving MR contrast medium. Single-photon emission computed tomography and CXA were performed within 4 weeks before or after CMR in all patients. The prevalence of CAD in the sample was 49%. Drop-out rates for CMR and SPECT were 5.6 and 3.7%, respectively (P = 0.21). The primary endpoint was non-inferiority of CMR vs. SPECT for both sensitivity and specificity for the detection of CAD. Readers were blinded vs. clinical data, CXA, and imaging results. As a secondary endpoint, the safety profile of the CMR examination was evaluated. For CMR and SPECT, the sensitivity scores were 0.67 and 0.59, respectively, with the lower confidence level for the difference of +0.02, indicating superiority of CMR over SPECT. The specificity scores for CMR and SPECT were 0.61 and 0.72, respectively (lower confidence level for the difference: -0.17), indicating inferiority of CMR vs. SPECT. No severe adverse events occurred in the 515 patients. CONCLUSION: In this large multicentre, multivendor study, the sensitivity of perfusion-CMR to detect CAD was superior to SPECT, while its specificity was inferior to SPECT. Cardiac magnetic resonance is a safe alternative to SPECT to detect perfusion deficits in CAD.

Superior diagnostic performance of perfusion-cardiovascular magnetic resonance versus SPECT to detect coronary artery disease: The secondary endpoints of the multicenter multivendor MR-IMPACT II (Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial).

BACKGROUND: Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. The goal was to compare in a multicenter setting the diagnostic performance of perfusion-CMR and gated-SPECT for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference. METHODS: In 33 centers (in US and Europe) 533 patients, eligible for CXA or SPECT, were enrolled in this multivendor trial. SPECT and CXA were performed within 4 weeks before or after CMR in all patients. Prevalence of CAD in the sample was 49% and 515 patients received MR contrast medium. Drop-out rates for CMR and SPECT were 5.6% and 3.7%, respectively (ns). The study was powered for the primary endpoint of non-inferiority of CMR vs SPECT for both, sensitivity and specificity for the detection of CAD (using a single-threshold reading), the results for the primary endpoint were reported elsewhere. In this article secondary endpoints are presented, i.e. the diagnostic performance of CMR versus SPECT in subpopulations such as multi-vessel disease (MVD), in men, in women, and in patients without prior myocardial infarction (MI). For diagnostic performance assessment the area under the receiver-operator-characteristics-curve (AUC) was calculated. Readers were blinded versus clinical data, CXA, and imaging results. RESULTS: The diagnostic performance (= area under ROC = AUC) of CMR was superior to SPECT (p = 0.0004, n = 425) and to gated-SPECT (p = 0.018, n = 253). CMR performed better than SPECT in MVD (p = 0.003 vs all SPECT, p = 0.04 vs gated-SPECT), in men (p = 0.004, n = 313) and in women (p = 0.03, n = 112) as well as in the non-infarct patients (p = 0.005, n = 186 in 1-3 vessel disease and p = 0.015, n = 140 in MVD). CONCLUSION: In this large multicenter, multivendor study the diagnostic performance of perfusion-CMR to detect CAD was superior to perfusion SPECT in the entire population and in sub-groups. Perfusion-CMR can be recommended as an alternative for SPECT imaging. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT00977093.

MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial.

AIMS: To determine in a multicentre, multivendor trial the diagnostic performance for perfusion-cardiac magnetic resonance (perfusion-CMR) in comparison with coronary X-ray angiography (CXA) and single-photon emission computed tomography (SPECT). METHODS AND RESULTS: Of 241 eligible patients from 18 centres, 234 were randomly dosed with 0.01, 0.025, 0.05, 0.075, or 0.1 mmol/kg Gd-DTPA-BMA (Omniscantrade mark, GE-Healthcare) per stress (0.42 mg/kg adenosine) and rest perfusion study. Coronary artery disease (CAD) was defined as diameter stenosis > or =50% on quantitative CXA. Five CMR and eight SPECT studies (of 225 complete studies) were excluded from analyses due to inadequate quality (three blinded readers scored per modality). The comparison of CMR vs. SPECT was based on receiver operating characteristic (ROC) analysis. Perfusion-CMR at the optimal CM dose (0.1 mmol/kg) had similar performance as SPECT, if only the SPECT studies of the 42 patients with this dose were considered [area under ROC curve (AUC): 0.86 +/- 0.06 vs. 0.75 +/- 0.09 for SPECT, P = 0.12]; however, diagnostic performance of perfusion-CMR was better vs. the entire SPECT population (AUC: 0.67 +/- 0.05, n = 212, P = 0.013). CONCLUSIONS: In this multicentre, multivendor trial, ROC analyses suggest perfusion-CMR as a valuable alternative to SPECT for CAD detection showing equal performance in the head-to-head comparison. Comparing perfusion-CMR with the entire SPECT population suggests CMR superiority over SPECT, which warrants further evaluation in larger trials.

Sequential changes of myocardial function during acute myocardial infarction, in the early and chronic phase after coronary intervention described by ultrasonic strain rate imaging.

OBJECTIVE: The aim of this prospective clinical study was to follow up patients with acute myocardial infarction from the ischemic event, over the primary coronary intervention (PCI), up to the chronic phase after survived myocardial infarction by noninvasive strain rate (SR) imaging and to determine its role in the assessment of transmurality of infarction. METHODS: In all, 41 patients with acute S-T elevation infarction were examined immediately before, 3 days after, and 5 months after PCI. Regional myocardial function was assessed by the use of ultrasonic SR imaging and peak systolic SR and systolic strain were extracted. In addition, late-enhancement (LE) imaging with magnetic resonance imaging was done after 5 months to assess the transmurality of residual scar distribution. RESULTS: Magnetic resonance imaging showed that 8 patients had no LE (complete recovery = no-scar group), 16 patients had subendocardial LE (nontransmural infarction = NT group), and 17 patients had a transmural LE (transmural infarction = T group) in the region of interest. Before PCI both SR and strain were markedly reduced in the ischemic segments compared with the nonischemic remote region in all 3 groups (SR: ischemia = -0.6 +/- 0.3 s(-1); remote = -1.3 +/- 0.4 s(-1), P < .001). Three days after PCI, systolic SR only increased significantly in the regions that were not transmurally infarcted. After 5 months the measurement of systolic strain could accurately distinguish the different groups. (no-scar group = -24 +/- 5%, NT group = -13 +/- 4%, T group = -1 +/- 3%). CONCLUSIONS: This clinical study shows that with SR imaging: (1) the ischemic segment can be precisely detected; (2) the absence of transmurality early after coronary intervention can be predicted; and (3) in the chronic phase the transmurality of scar distribution can be assessed.

Myocardial perfusion measurements by spin-labeling under different vasodynamic states.

In this study absolute myocardial perfusion was determined using a spin-labeling magnetic resonance imaging (MRI) technique at 2 Tesla. The technique was applied to 16 healthy volunteers at resting conditions, adenosine-induced stress, and oxygen breathing. Overall myocardial quantitative perfusion was determined as 2.3 +/- 0.8 mL/g/min (rest), 4.2 +/- 1.0 mL/g/min (adenosine), and 1.6 +/- 0.6 mL/g/min (oxygen), respectively. T1 of left ventricular blood pool decreased from 1709 +/- 101 ms (rest) to 1423 +/- 61 ms (oxygen), whereas T1 of right ventricular blood did not change significantly (1586 +/- 126 ms and 1558 +/- 150 ms). In conclusion, the presented technique for quantification of myocardial perfusion is an alternative to contrast agent-based methods. The spin labeling method is noninvasive and easily repeatable and it could therefore become an important tool to study changes in myocardial perfusion under different vasodynamic states.

Quantitative assessment of myocardial perfusion with a spin-labeling technique: preliminary results in patients with coronary artery disease.

PURPOSE: To determine perfusion and coronary reserve in human myocardium without contrast agent using a spin labeling technique. MATERIALS AND METHODS: Assessment of myocardial perfusion is based on T1 measurements after global and slice-selective spin preparation. This magnetic resonance imaging (MRI) technique was applied to 12 healthy volunteers and 16 patients with suspected coronary artery disease under resting conditions and adenosine-induced vasodilatation. RESULTS: In volunteers, quantitative perfusion was calculated as 2.4 +/- 1.2 mL/g/minute (rest) and 3.9 +/- 1.3 mL/g/minute (adenosine), respectively. Perfusion reserve was 2.1 +/- 0.6. In patients, when comparing perfusion reserve in the anterior and posterior myocardium, reduced values according to a stenotic supplying vessel could be seen in seven of 11 patients who underwent stress testing. In these patients, the relative difference of coronary reserve was 44% +/- 18%. Two patients without stenosis of coronary arteries showed no differences in coronary reserve (with a relative change of 2 +/- 2%). CONCLUSION: In patients with single-vessel coronary artery disease, differences in coronary reserve were clearly detectable when comparing anterior and posterior myocardium. The spin labeling method is noninvasive and easily repeatable, and it could therefore become an important tool to study changes in myocardial perfusion.

[Myocardial microcirculation in humans--new approaches using MRI]. / Neue Ansätze der Magnetresonanztomographie zur Beschreibung myokardialer Mikrozirkulationsparameter am Menschen.

INTRODUCTION: One crucial goal of magnetic resonance imaging (MRI) in patients with coronary artery disease (CAD) is the characterization of myocardial microcirculation that reflects tissue supply much better than detection and quantification of a stenosis itself. PERFUSION: Myocardial perfusion is one important parameter of microcirculation and it is commonly detected by first-pass techniques using contrast agents (CA). Despite the quantification of perfusion it is an indispensable component of a comprehensive diagnosis to determine the perfusion reserve, which is believed a good indicator for viability of myocardium. However, most MRI techniques for perfusion imaging are Ca based and this implies a restricted reproducibility in humans. Beyond it, most first-pass techniques are qualitative and not quantitative. REGIONAL BLOOD VOLUME: Another parameter of microcirculation is the regional intracapillary myocardial blood volume (RBV) that almost represents the whole intramyocardial blood volume due to its dominating volume fraction. The RBV reflects the autoregulatory adaptation of microvessels, e.g., a severe stenosis may lead to an increase of the RBV by capillary recruitment, and the RBV is reduced in scar areas. The RBV may be quantified by first-pass techniques; however, this demands a definite relation between signal intensity and concentration of the CA, which is difficult to find for the range of concentrations present during the first pass. Until recently, no techniques existed for the exact and noninvasive assessment of the RBV. CAPILLARY RECRUITMENT: The evaluation of the relevance of a coronary artery stenosis is of paramount interest for the therapeutic decision. A severe stenosis implies the activation of compensation mechanisms, which includes poststenotic dilation of the microvascular system. This lowering of the vascular resistance aims to maintain sufficient blood supply at least under resting conditions. However, many obstacles hamper the noninvasive assessment of this autoregulatory response so far. Our laboratory recently developed different techniques for the assessment of myocardial perfusion, regional myocardial blood volume, and capillary recruitment. These techniques are based on theoretical and physiologic considerations and work mainly without CA. In this article, feasibility and reproducibility of these approaches are shown in volunteers and patients. CLINICAL STUDIES: MR exams were performed on a 1.5-T whole body scanner (SIEMENS Vision) and a 2-T system (BRUKER Tomikon). Stress examinations were done repeatedly under pharmacologically induced stress (dipyridamole or adenosine, infusion rate: 0.56 mg/kg body weight over 4 min via an antecubital vein). Heart rate and blood pressure were continuously monitored during stress exams. T1 MEASUREMENTS: Spin labeling used in this work is based on T1 measurements after global and slice-selective spin preparation using a fast ECG-gated saturation recovery FLASH sequence. Due to the inflow of unsaturated proton spins, T1 in tissue is shortened after slice-selective preparation case compared to global saturation. We showed that, assuming a two compartment model with fast proton exchange between the compartments, the absolute perfusion P (in [ml/g/min]) can be calculated as P = lambda/T1(blood) ([T1(global)/T1(selective)] - 1), where the blood tissue partition coefficient lambda represents the quotient of water content of capillary blood and perfused tissue, which is approximately 0.9 ml/g in myocardial tissue. T1(blood) is the longitudinal relaxation time T1 of the arterial blood, measured in the left ventricle (LV). T1(global) and T1(selective) are the myocardial T1 calculated after the respective spin preparation. Perfusion reserve is evaluated as the quotient of perfusion under adenosine-induced stress and perfusion at rest. In volunteers quantitative perfusion was determined as 2.5 +/- 0.7 ml/g/min (rest), perfusion reserve was about 2.0. Absolute perfusion decreased to 1.6 +/- 0.6 ml/g/min under oxygen breathing. In patients with CAD, myocardial regions with decreased perfusion reserve could be identified. perfusion reserve could be identified. Performing the described spin-labeling technique with an intravascular CA facilitates the determination of the intra-extracapillary water proton exchange frequency and the RBV. In a patient study, the effect of the intravascular CA Feruglose (Amersham) on relaxation rate in myocardium (R1(myo)) in the steady state was investigated (Figure 1). The dependence of R1(myo) on R1(blood) was characterized and compared with a theoretical model which allowed determination of the intra-extracapillary water proton exchange frequency (f = 0.48 s(-1)) and the intracapillary blood volume (RBV = 12.9%). A linear response range of Delta R1(myo) on Delta R1(blood) was estimated which, in future studies, will allow the determination of RBV with intravascular CA (Figure 2). T2* MEASUREMENTS: We anticipated that poststenotic vasodilatation implies a capillary recruitment. Almost all (i.e., > 90%) of intramyocardial blood residues in that type of vessel. Due to their large arteriovenous oxygenation difference, myocardial capillaries contain considerable amounts of deoxyhemoglobin (Figure 3). Hence, in regions with autoregulatory capillary recruitment the tissue concentration of deoxyhemoglobin should be elevated when compared to myocardium supplied by a normal vessel (Figure 5b). Due to its paramagnetic property and its intravascular confinement, the natural CA deoxyhemoglobin may be assessed by susceptibility sensitive, or also called blood oxygenation level-dependent (BOLD) MRI. For T2* measurements, a segmented gradient echo pulse sequence was used, which acquired ten successive gradient echoes per rf excitation in a single breathhold. In volunteers, there was an increase in T2* of about 10% under dipyridamole-induced stress (Figure 4). This means a decrease of the intracapillary deoxyhemoglobin concentration, whereas the oxygen consumption under increased perfusion did not change. In myocardial regions of patients, associated with the stenotic artery T2* was significantly lower than in residual myocardium (p < 0.01; Figure 5a). This difference in T2* increased after application of the vasodilator dipyridamole (p < 0.001). In patients being reinvestigated after therapeutic interventions, the microvascular dilation was partly removed (Figure 5c). For the first time we could show that myocardial BOLD MRI detects poststenotic capillary recruitment dependent on a coronary artery stenosis.

Susceptibility-sensitive magnetic resonance imaging detects human myocardium supplied by a stenotic coronary artery without a contrast agent.

OBJECTIVES: Evaluation of the severity of a coronary artery stenosis is of paramount importance for therapy. A relevant stenosis provokes post-stenotic microvascular dilation with capillary recruitment. This autoregulatory response was investigated in the present study by use of susceptibility-sensitive magnetic resonance imaging (MRI) without contrast agents. BACKGROUND: Functional alterations of the microvascular system may be studied noninvasively and without a contrast agent by susceptibility-sensitive MRI, which is based on the paramagnetic property of deoxyhemoglobin. This effect, also referred to as the "blood oxygenation level-dependent (BOLD) effect," is investigated by phase relaxation (T(2)*) measurements. METHODS: In patients (n = 16) with single-vessel coronary artery disease, no history of myocardial infarction, normal left ventricular function at rest, and a positive stress echocardiogram, the susceptibility-sensitive parameter T(2)* was assessed in the myocardium. RESULTS: In regions associated with the stenotic artery, T(2)* was significantly lower than in residual myocardium (p < 0.01). This difference in T(2)* increased after application of the vasodilator dipyridamole (p < 0.001). In patients being re-investigated after therapeutic interventions, the microvascular dilation was partly removed. CONCLUSIONS: For the first time, we could show that myocardial BOLD MRI detects post-stenotic capillary recruitment dependent on coronary artery stenosis.

Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pretreatment with aspirin and clopidogrel (TOPSTAR trial).

OBJECTIVES: The Troponin in Planned PTCA/Stent Implantation With or Without Administration of the Glycoprotein IIb/IIIa Receptor Antagonist Tirofiban (TOPSTAR) trial investigated: 1) the amount of troponin T (TnT) release after nonacute, elective percutaneous coronary intervention (PCI) in patients pretreated with aspirin and clopidogrel; and 2) the effect of additional glycoprotein (GP) IIb/IIIa receptor inhibiton on postinterventional TnT release. BACKGROUND: No data are available yet as to whether additional administration of a GP IIb/IIIa receptor antagonist might be beneficial in patients undergoing elective PCI already pretreated with aspirin and clopidogrel. METHODS: After bolus application of the study medication (tirofiban [T] or placebo [P]), PCI was performed followed by an 18-h continuous infusion of T/P. Primary end point of the study was incidence and amount of TnT release after elective PCI after 24 h. RESULTS: A total of 12 h after PCI troponin release was detected in 63% of the patients receiving P and in 40% of the patients receiving T (p < 0.05), after 24 h in 69% (P) and 48% (T) (p < 0.05) and after 48 h in 74% (P) versus 58% (T) (p < 0.08) of the patients. No differences were observed regarding major bleeding, intracranial bleeding or nonhemorrhagic strokes. After nine months a reduction of combined death/myocardial infarction/target vessel revascularization could be observed in the tirofiban group ([T] 2.3% vs. [P] 13.04%, p < 0.05). CONCLUSIONS: Troponin T release occurs after successful intervention in 74% of the patients undergoing elective PCI after 48 h even after pretreatment with aspirin and clopidogrel. The GP IIb/IIIa receptor antagonist tirofiban is able to decrease the incidence of troponin release significantly in this patient population.

Determination of regional blood volume and intra-extracapillary water exchange in human myocardium using Feruglose: First clinical results in patients with coronary artery disease.

The aim of this pilot study in humans was to investigate the effect of an intravascular contrast agent (CA) on relaxation rate in myocardium (R(1,myo)) in the steady state. The dependence of R(1,myo) on R(1,blood) was characterized and compared with a theoretical model which allowed determination of the intra- extracapillary water proton exchange frequency (f = 0.48 s(-1)) and the intracapillary blood volume (RBV = 12.9 %). A linear response range of DeltaR(1,myo) on DeltaR(1,blood) was estimated which in future studies will allow the determination of RBV with intravascular CA.