Continuous real-time biofeedback in orthosis improves partial weight bearing on stairs.

INTRODUCTION: Climbing up and down stairs with crutches is a particular challenge. The current study evaluates a commercially available insole orthosis device for weighing an affected limb and for biofeedback training of gait. This study was done on healthy, asymptomatic individuals before applying to the intended postoperative patient. The outcomes should demonstrate whether a continuous real-time biofeedback (BF) system is more effective on stairs than the current protocol involving a bathroom scale. MATERIALS AND METHODS: 59 healthy test subjects received both crutches and an orthosis and learned to apply a 3-point gait with a partial load of 20 kg using a bathroom scale. Thereafter, the participants were asked to complete an up-and-down course, first without (control group) and then with (test group) an audio-visual real-time biofeedback (BF). Compliance was evaluated using an insole pressure measurement system. RESULTS: Using the conventional therapy technique, 36.6% of the steps up and 39.1% of the steps down in the control group were loaded with < 20 kg. By activating continuous biofeedback, steps with < 20 kg could be increased significantly to 61.1% upstairs (p < 0.001) and 66.1% downstairs (p < 0.001). All subgroups profited from the BF system, independent of age, gender, side relieved, dominant or non-dominant side. CONCLUSIONS: Traditional training without biofeedback led to poor performance for partial weight bearing on stairs, even among young and healthy individuals. However, continuous real-time biofeedback clearly improved compliance, indicating its potential to enhance training and support future research in patient populations.

Can elderly individuals perform partial weight bearing on their lower limbs? A prospective cohort study using ambulatory real-time biofeedback.

BACKGROUND: Partial weight bearing in an orthosis and with forearm crutches is a widespread and well-accepted therapeutic principle after an injury of the lower extremity during early rehabilitation. Complying may be challenging to do under these circumstances, especially for elderly people. This study compares the spatiotemporal parameters and peak loads performed by a group of older participants before and after activating real-time biofeedback (BF) to determine whether they benefit from a biofeedback. METHODS: Twenty-four healthy subjects between 61 and 80 years learned how to walk using forearm crutches in a lower leg orthosis while performing a weight of 20 kg using a bathroom scale with the aim of loading in a zone between 15 and 30 kg. After that, they completed a course that was on level ground (50 m) and another course on stairs (11 steps). They did a walk without BF first, and then with BF. Each step was given a maximum load, which was determined and statistically checked. In addition, spatiotemporal parameters were collected. RESULTS: The classical teaching method with a bathroom scale was ineffective. Only 32.3% of the loads could be adequately carried by a person on level ground in the 15-30 kg target zone. On the stairs, it was 48.2% and 34.3%, respectively. Thus, on level ground, 52.7% of loads exceeded 30 kg. Downstairs it was 46.4%, and upstairs it was 41.6%. Subjects clearly benefit from activated biofeedback. Biofeedback significantly reduced missteps > 30 kg in every course. The loads decreased significantly to 25.0% on level ground, to 23.0% upstairs, and to 24.4% downstairs. At the same time, speed and stride length decreased per course while total time increased. CONCLUSION: Partial weight bearing is more complex and difficult for the elderly. These study results may help better understand 3-point gait in older adults in an outpatient setting. When partial weight bearing is recommended, special follow-up attention must be given for this group. Age-based therapy strategies can be developed and monitored with the assistance of ambulatory biofeedback devices. Trial registration Retrospectively registered, https://www.drks.de/DRKS00031136 .

The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.

BACKGROUND: Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. METHODS: We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. RESULTS: Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. CONCLUSIONS: These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.

Calcineurin inhibitors in systemic sclerosis - a systematic literature review.

Objective: To review treatment effectiveness and adverse events of calcineurin inhibitors (CNIs) such as cyclosporin A (CsA) and tacrolimus in patients with systemic sclerosis (SSc). Methods: A systematic literature search was performed on PubMed and Web of Science using the predefined keywords 'systemic sclerosis', scleroderma, cyclosporin*, and tacrolimus. Articles were eligible for inclusion, if SSc patients had been treated with CNIs and data on treatment effects were available. Results: This systematic literature review identified 37 papers (19 case reports, 15 case series, 2 controlled studies, and 1 retrospective study) including 134 SSc patients treated with CNIs. In 34 of 37 papers, CsA was used. An improvement of skin fibrosis was observed in 77 of 96 (80.2%) patients using a wide variety of outcome measures and dose regimes. Both controlled studies showed significant improvements, one using a historical control group and one using a no-treatment control group. Improvement in pulmonary function tests (PFTs) occurred in 67.9% (19/28) of the patients who had reduced PFTs at baseline. In 58 (43.3%) cases, adverse renal events were reported, of which 7 (5.2%) were severe such as scleroderma renal crisis (SRC), CsA-associated nephropathy, or death by renal insufficiency. Adverse events led to dose reduction, treatment interruption, or withdrawal in 39 of 134 (29.1%). Conclusion: In this systematic literature review, signals for potential effectiveness of CsA for skin and pulmonary fibrosis were found, but the evidence level of the identified studies was too low to allow robust conclusions. Randomized controlled double-blind trials are needed to conclude on the effectiveness of CNIs in SSc. Renal toxicity of CNIs was confirmed in this review and needs to be considered in the design of such studies.

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein - WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells.

Mechanisms of WNT and bone morphogenetic protein (BMP) signaling crosstalk is in the focus of multiple biological studies, and it also has been discovered to play important roles in human mesenchymal stromal cells (MSC) that are of great interest for neocartilage engineering due to their high chondrogenic differentiation potential. However, MSC-derived chondrocytes undergo hypertrophic degeneration that impedes their clinical application for cartilage regeneration. In our previous study, we established that several microRNAs (miRs) are differentially expressed between articular chondrocytes (AC) - and MSC-derived neocartilage, with miR-181a being the most prominent candidate as key microRNA involved in the regulation of a balance between chondral and endochondral differentiation. The aim of this study was the identification of precise mRNA targets and signaling pathways regulated by miR-181a in MSC during chondrogenesis. MiR-181a was upregulated during chondrogenesis of MSC, along with an increase of the hypertrophic phenotype in resulting cartilaginous tissue. By in silico analysis combined with miR reporter assay, the WNT signaling activator and BMP signaling repressor RSPO2 was suggested as a target of miR-181a. Further validation experiments confirmed that miR-181a targets RSPO2 mRNA in MSC. It was found that in human MSC miR-181a activated BMP signaling manifested by the accumulation of SOX9 protein and increased phosphorylation of SMAD1/5/9. These effects, together with the concomitant reduction of canonical WNT signaling induced by miR-181a mimic, were in accordance with the effects expected by the loss of RSPO2, thus indicating the causative link between miR-181a and RSPO2. Moreover, we observed that a tight correlation between miR-181a and miR-218 expression levels in healthy human cartilage tissue was disrupted in osteoarthritis (OA) highlighting the importance of the WNT-BMP signaling crosstalk for preventing OA.

Multi-level inhibition of coronavirus replication by chemical ER stress.

Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types including primary differentiated human bronchial epithelial cells, (partially) reverses the virus-induced translational shut-down, improves viability of infected cells and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide analyses revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including essential (HERPUD1) or novel (UBA6 and ZNF622) factors of ER quality control, and ER-associated protein degradation complexes. Additionally, thapsigargin blocks the CoV-induced selective autophagic flux involving p62/SQSTM1. The data show that thapsigargin hits several central mechanisms required for CoV replication, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.

MiR-218 affects hypertrophic differentiation of human mesenchymal stromal cells during chondrogenesis via targeting RUNX2, MEF2C, and COL10A1.

BACKGROUND: Human mesenchymal stromal cells (MSC) hold hopes for cartilage regenerative therapy due to their chondrogenic differentiation potential. However, undesirable occurrence of calcification after ectopic transplantation, known as hypertrophic degeneration, remains the major obstacle limiting application of MSC in cartilage tissue regeneration approaches. There is growing evidence that microRNAs (miRs) play essential roles in post-transcriptional regulation of hypertrophic differentiation during chondrogenesis. Aim of the study was to identify new miR candidates involved in repression of hypertrophy-related targets. METHODS: The miR expression profile in human articular chondrocytes (AC) was compared to that in hypertrophic chondrocytes derived from human MSC by microarray analysis, and miR expression was validated by qPCR. Putative targets were searched by in silico analysis and validated by miR reporter assay in HEK293T, by functional assays (western blotting and ALP-activity) in transiently transfected SaOS-2 cells, and by a miR pulldown assay in human MSC. The expression profile of miR-218 was assessed by qPCR during in vitro chondrogenesis of MSC and re-differentiation of AC. MSC were transfected with miR-218 mimic, and differentiation outcome was assessed over 28 days. MiR-218 expression was quantified in healthy and osteoarthritic cartilage of patients. RESULTS: Within the top 15 miRs differentially expressed between chondral AC versus endochondral MSC differentiation, miR-218 was selected as a candidate miR predicted to target hypertrophy-related genes. MiR-218 was downregulated during chondrogenesis of MSC and showed a negative correlation to hypertrophic markers, such as COL10A1 and MEF2C. It was confirmed in SaOS-2 cells that miR-218 directly targets hypertrophy-related COL10A1, MEF2C, and RUNX2, as a gain of ectopic miR-218 mimic caused drop in MEF2C and RUNX2 protein accumulation, with attenuation of COL10A1 expression and significant concomitant reduction of ALP activity. A miR pulldown assay confirmed that miR-218 directly targets RUNX2, MEF2C in human MSC. Additionally, the gain of miR-218 in human MSC attenuated hypertrophic markers (MEF2C, RUNX2, COL10A1, ALPL), although with no boost of chondrogenic markers (GAG deposition, COL2A1) due to activation of WNT/ß-catenin signaling. Moreover, no correlation between miR-218 expression and a pathologic phenotype in the cartilage of osteoarthritis (OA) patients was found. CONCLUSIONS: Although miR-218 was shown to target pro-hypertrophic markers MEF2C, COL10A1, and RUNX2 in human MSC during chondrogenic differentiation, overall, it could not significantly reduce the hypertrophic phenotype or boost chondrogenesis. This could be explained by a concomitant activation of WNT/ß-catenin signaling counteracting the anti-hypertrophic effects of miR-218. Therefore, to achieve a full inhibition of the endochondral pathway, a whole class of anti-hypertrophic miRs, including miR-218, needs to be taken into consideration.

Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice.

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection.Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model.Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection.

Splenic Switch-Off for Determining the Optimal Dosage for Adenosine Stress Cardiac MR in Terms of Stress Effectiveness and Patient Safety.

BACKGROUND: Adenosine stress MRI is well established for the evaluation of known and suspected coronary artery disease. However, a proportion of patients might be "under-stressed" using the standard adenosine dose. PURPOSE: To compare three different adenosine dosages for stress MRI in terms of stress adequacy based on splenic switch-off (SSO) and limiting side effects. STUDY TYPE: Prospective. POPULATION: In all, 100 patients were randomized in group 1 (33 pts), group 2 (34 pts), and group 3 (33 pts), receiving dosages of 140 µg/kg/min, 175 µg/kg/min, or 210 µg/kg/min, respectively. SSO was evaluated visually and quantitatively. SEQUENCE: Stress perfusion was performed using a 1.5T scanner in three short axes using a standard single-shot, saturation recovery gradient-echo sequence. ASSESSMENT: Three blinded experienced operators evaluated SSO on stress and rest perfusion acquisitions in the three groups. The signal intensity of the spleen and myocardium and the presence of inducible ischemia and late gadolinium enhancement were assessed. STATISTICAL ANALYSIS: T-test, analysis of variance (ANOVA), chi-squared test, and Pearson's correlation coefficient. RESULTS: SSO was present more frequently in patients receiving 175 µg/kg/min and 210 µg/kg/min (31/33 [94%] and 27/29 [93%], respectively) compared to those receiving the standard dose (19/33 [58%], P < 0.05). A positive stress result was noted in 3/33 (9%) patients receiving 140 µg/kg/min vs. 9/33 (27%) patients receiving 175 µg/kg/min and 10/31 (33%) patients receiving 210 µg/kg/min (P < 0.05 for all, P < 0.05 for group 1 vs. groups 2, 3). The relative decrease of splenic signal intensity at hyperemia vs. baseline was significantly lower in group 1 compared to groups 2 and 3 (-33% vs. -54%, -56%, respectively; P < 0.05). No adverse events during scanning were noted in groups 1 and 2, whereas in group 3 four examinations were stopped due to severe dyspnea (n = 2) and AV-blockage (n = 2). DATA CONCLUSION: A dosage of 175 µg/kg/min adenosine results in a higher proportion of SSO, which may be an indirect marker of adequate coronary vasodilatation and simultaneously offers similar safety compared to the standard 140 µg/kg/min dosage. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2 J. MAGN. RESON. IMAGING 2020;52:1732-1742.

Strain-encoded magnetic resonance: a method for the assessment of myocardial deformation.

This study aims to assess the usefulness of strain-encoded magnetic resonance (SENC) for the quantification of myocardial deformation ('strain') in healthy volunteers and for the diagnostic workup of patients with different cardiovascular pathologies. SENC was initially described in the year 2001. Since then, the SENC sequence has undergone several technical developments, aiming at the detection of strain during single-heartbeat acquisitions (fast-SENC). Experimental and clinical studies that used SENC and fast-SENC or compared SENC with conventional cine or tagged magnetic resonance in phantoms, animals, healthy volunteers, or patients were systematically searched for in PubMed. Using 'strain-encoded magnetic resonance and SENC' as keywords, three phantom and three animal studies were identified, along with 27 further clinical studies, involving 185 healthy subjects and 904 patients. SENC (i) enabled reproducible assessment of myocardial deformation in vitro, in animals and in healthy volunteers, (ii) showed high reproducibility and substantially lower time spent compared with conventional tagging, (iii) exhibited incremental value to standard cine imaging for the detection of inducible ischaemia and for the risk stratification of patients with ischaemic heart disease, and (iv) enabled the diagnostic classification of patients with transplant vasculopathy, cardiomyopathies, pulmonary hypertension, and diabetic heart disease. SENC has the potential to detect a wide range of myocardial diseases early, accurately, and without the need of contrast agent injection, possibly enabling the initiation of specific cardiac therapies during earlier disease stages. Its one-heartbeat acquisition mode during free breathing results in shorter cardiovascular magnetic resonance protocols, making its implementation in the clinical realm promising.

Image quality and contrast agent exposure in cardiac computed tomography angiography prior to transcatheter aortic valve implantation procedures using different acquisition protocols.

BACKGROUND: ECG-gated cardiac computed tomography angiography (CCTA) has found widespread use for prosthesis sizing before transcatheter aortic valve implantation (TAVI). However, still little data exists on the optimal scan-strategy in such patients. We hypothesized that prospectively triggered CCTA can enable the visualization of aortic valve structures and peripheral arteries with lower radiation and contrast agent exposure in patients considered for TAVI compared to retrospectively gated protocols. METHODS: All studies were performed using a 256 multi-detector single source CT (iCT Philips, Best, Netherlands). With the prospective protocol the whole volume from the heart to the iliofemoral arteries scanned using prospective triggering. With the retrospective protocol a first retrospectively gated scan was performed for the heart and the iliofemoral part was subsequently scanned using a second non-triggered scan. Image quality was assessed semi-quantitatively and signal-to-noise- (SNR) and contrast-to-noise-ratios (CNR) were obtained for all scans. RESULTS: Prospective CCTA was performed in 74 and in 34 patients, respectively using non-tailored and BMI adapted scans, whereas retrospective CCTA was performed in 57 patients. Prospective scans required lower contrast agent administration compared to retrospective scans (71 ± 8 mL versus 91 ± 15 mL, p < 0.01) and resulted in lower radiation exposure (26 ± 7mSv for retrospective versus 15 ± 3mSv for non-tailored prospective versus 8 ± 4mSv for BMI-adapted prospective scans, p < 0.01). Visual image quality was better for the evaluation of aortic valve structures and similar for the assessment of iliofemoral anatomy with prospective versus retrospective scans. In addition, contrast density, SNR and CNR were higher in the ascending aorta with prospective versus retrospective CCTA (434 ± 98HU versus 349 ± 112HU; 35 ± 14 versus 24 ± 9 and 31 ± 11 versus 16 ± 7, p < 0.001 for all). Subsection analysis by heart rate groups demonstrated that both image quality and CNR were significantly higher in patients with prospective versus retrospective CCTA, irrespective of the heart rate during image acquisition. CONCLUSION: Prospectively triggered CCTA allows for improved visualization of aortic valve structures and peripheral arteries in patients scheduled for TAVI with simultaneously reduced contrast agent dose and radiation exposure. Therefore, this acquisition mode seems to be the preferred for the evaluation of patients considered for TAVI.

Quantitative myocardial blush grade reserve during pharmacologic hyperaemia: a way to perform a real wireless fractional flow reserve measurement in patients with coronary artery disease and intermediate coronary lesions.

AIMS: We investigated the relation between myocardial blush grade reserve (MBGreserve) and fractional flow reserve (FFR) measures. FFR is a marker of inducible myocardial ischaemia, which could guide percutaneous coronary intervention (PCI) and stent placement. However, it requires a pressure wire and is associated with additional costs and potential hazards. The aim of our study was to investigate the ability of MBG for the evaluation of functional significance in intermediate coronary lesions during pharmacologic hyperaemia. METHODS AND RESULTS: Fifty-six patients who underwent routine cardiac catheterisation for known or suspected coronary artery disease (CAD) and clinically indicated FFR measures in at least one coronary vessel were analysed. MBGreserve was assessed at baseline and during pharmacologic hyperaemia. Video densitometric parameters were then calculated by the ratio of maximal density (Gmax) and the time to reach maximum density (Tmax). Gmax/Tmax during hyperaemia divided by Gmax/Tmax at baseline provided the MBGreserve. A significant association was observed between MBGreserve and FFR. A cut-off value of MBGreserve=2.1 demonstrated sensitivity of 80% and specificity of 96% for the prediction of abnormal FFR of ≤0.8. MBGreserve increased in coronary territories that underwent PCI, reaching similarly high values compared to those observed in FFR-negative lesions. CONCLUSIONS: Quantitative MBGreserve is closely related to FFR measures and may obviate the need for pressure wire measurements in the interests of patient safety, time and costs.

Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis.

Left ventricular (LV) hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG), echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m(2)), severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%), accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease.

Myocardial Perfusion Reserve and Strain-Encoded CMR for Evaluation of Cardiac Allograft Microvasculopathy.

OBJECTIVES: This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy. BACKGROUND: Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. METHODS: Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. RESULTS: Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). CONCLUSIONS: CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.

Combined Assessment of High-Sensitivity Troponin T and Noninvasive Coronary Plaque Composition for the Prediction of Cardiac Outcomes.

PURPOSE: To determine the risk-stratification ability of plaque volume and composition assessment with cardiac computed tomographic (CT) angiography and high-sensitivity troponin T (hsTnT) in patients at intermediate risk for coronary artery disease (CAD). MATERIALS AND METHODS: The study complied with the Declaration of Helsinki and was approved by the local ethics committee. All patients gave written informed consent. Five hundred twenty-one consecutive patients (mean age ± standard deviation, 62 years ± 10; 256 men and 265 women) were included in this prospective, observational, longitudinal, single-center study. Quantitative cardiac CT angiography analysis was performed in all patients (for 7690 coronary segments), whereas biomarkers (hsTnT and high-sensitivity C-reactive protein) were available in 408 patients (78%). To evaluate the incremental value of cardiac CT angiography and hsTnT for the prediction of cardiovascular events, multivariate Cox regression and integrated discrimination improvement analysis were applied. RESULTS: In 521 patients, 13 hard cardiac events occurred during a mean follow-up period of 2.3 years ± 1.1 (median, 2.4 years; range, 0.5-4.5 years), while 23 patients underwent late coronary revascularization. The Duke clinical score was 51% ± 30, indicating intermediate risk. The presence of no plaques or purely calcified versus noncalcified plaques, plaque volume according to tertiles, and increased hsTnT (≥14 pg/mL) was independently associated with hard cardiac events (hazard ratio [HR] = 26.08, 95% confidence interval [CI]: 2.78, 244.99; HR = 12.14, 95% CI: 1.87, 78.74; and HR = 10.31, 95% CI: 2.72, 39.0, respectively; P < .01 for all). Patients with increased hsTnT and plaque burden (n = 53) showed the highest incidence for hard cardiac events (annual rate, 12.7%), followed by those with either increased hsTnT or plaque burden (n = 145; annual rate = 0.44%, P < .03), while those with lower hsTnT and plaque burden exhibited excellent outcomes and no hard event during the follow-up duration (n = 210; annual rate = 0%, P < .001). CONCLUSION: Use of hsTnT as a marker of myocardial microinjury and cardiac CT angiography as a marker of the total atherosclerotic burden improves the prediction of cardiac outcome in patients with presumably stable CAD and may aid in personalized risk stratification in patients at intermediate risk.

The extent of aortic annulus calcification is a predictor of postprocedural eccentricity and paravalvular regurgitation: a pre- and postinterventional cardiac computed tomography angiography study.

PURPOSE: To investigate if the extent of aortic valve calcification is associated with postprocedural prosthesis eccentricity and paravalvular regurgitation (PAR) in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: Cardiac computed tomography angiography (CCTA) was performed before and 3 months after TAVI in 46 patients who received the self-expanding CoreValve and in 22 patients who underwent balloon-expandable Edwards Sapien XT implantation. Aortic annulus calcification was measured with CCTA prior to TAVI and prosthesis eccentricity was assessed with post-TAVI CCTA. Standard echocardiography was also performed in all patients at 3-month follow-up exam. RESULTS: Annulus eccentricity was reduced during TAVI using both implantation systems (from 0.23 ± 0.06 to 0.18 ± 0.07 using CoreValve and from 0.20 ± 0.07 to 0.05 ± 0.03 using Edwards Sapien XT; P<.001 for both). With Edwards Sapien XT, eccentricity reduction at the level of the aortic annulus was significantly higher compared with CoreValve (P<.001). Annulus eccentricity after CoreValve use was significantly related to absolute valve calcification and to valve calcification indexed to body surface area (BSA) (r = 0.48 and 0.50, respectively; P<.001 for both). Furthermore, a significant association was observed between aortic valve calcification and PAR (P<.01 by ANOVA) in patients who received CoreValve. Using ROC analysis, a cut-off value over 913 mm² aortic valve calcification predicted the occurrence of moderate or severe PAR with a sensitivity of 92% and a specificity of 63% (area under the curve = 0.75). Furthermore, multivariable analysis showed that aortic valve calcification was a robust predictor of postprocedural eccentricity and PAR, independent of the aortic annulus size and native valve eccentricity and of CoreValve prosthesis size (adjusted r = 0.46 and 0.50, respectively; P<.01 for both). Such associations were not present with the Edwards Sapien XT system. CONCLUSION: The extent of native aortic annulus calcification is predictive for postprocedural prosthesis eccentricity and PAR, which is an important marker for long-term mortality in patients undergoing TAVI. This observation applies for the CoreValve, but not for the Edwards Sapien XT valve.

Prediction of functional recovery by cardiac magnetic resonance feature tracking imaging in first time ST-elevation myocardial infarction. Comparison to infarct size and transmurality by late gadolinium enhancement.

PURPOSE: To investigate whether myocardial deformation imaging, assessed by feature tracking cardiac magnetic resonance (FTI-CMR), would allow objective quantification of myocardial strain and estimation of functional recovery in patients with first time ST-elevation myocardial infarction (STEMI). METHODS: Cardiac magnetic resonance (CMR) imaging was performed in 74 consecutive patients 2-4 days after successfully reperfused STEMI, using a 1.5T CMR scanner (Philips Achieva). Peak systolic circumferential and longitudinal strains were measured using the FTI applied to SSFP cine sequences and were compared to infarct size, determined by late gadolinium enhancement (LGE). Follow-up CMR at 6 months was performed in order to assess residual ejection fraction, which deemed as the reference standard for the estimation of functional recovery. RESULTS: During the follow-up period 53 of 74 (72%) patients exhibited preserved residual ejection fraction ≥50%. A cut-off value of -19.3% for global circumferential strain identified patients with preserved ejection fraction ≥50% at follow-up with sensitivity of 76% and specificity of 85% (AUC=0.86, 95% CI=0.75-0.93, p<0.001), which was superior to that provided by longitudinal strain (ΔAUC=0.13, SE=0.05, z-statistic=2.5, p=0.01), and non-inferior to that provided by LGE (ΔAUC=0.07, p=NS). Multivariate analysis showed that global circumferential strain and LGE exhibited independent value for the prediction of preserved LV-function, surpassing that provided by age, diabetes and baseline ejection fraction (HR=1.4, 95% CI=1.0-1.9 and HR=1.4, 95% CI=1.1-1.7, respectively, p<0.05 for both). CONCLUSIONS: Estimation of circumferential strain by FTI provides objective assessment of infarct size without the need for contrast agent administration and estimation of functional recovery with non-inferior accuracy compared to that provided by LGE.

Low levels of natural IgM antibodies against phosphorylcholine are independently associated with vascular remodeling in patients with coronary artery disease.

Low anti-phosphorylcholine (PC) IgM plasma levels have been associated with increased incidence of adverse events in coronary artery disease (CAD). The underlying mechanisms are unclear. We hypothesized that atheroprotection mediated by anti-PC IgM antibodies is associated with reduced vascular remodeling and therefore tested whether anti-PC IgM plasma levels independently predict vascular remodeling. In a prospective cross-sectional study, anti-PC IgM plasma levels were measured in 175 consecutive patients with suspected CAD undergoing cardiac computed tomography angiography. Plaque morphology was thoroughly analyzed. Vascular remodeling was defined by a change in the vessel diameter at the plaque site in comparison to the reference segment proximal to the lesion (reference diameter) of ≥10%. Mean age of the patients was 64.8 ± 10.7 years, 48.6% were female. In 98 patients CAD was diagnosed, 57 (58.2%) of which displayed non-obstructive CAD (stenosis <50%), whereas 41 (41.8%) exhibited obstructive CAD (stenosis ≥50%). In 34 of 98 (34.7%) CAD patients vascular remodeling was present. Mean anti-PC IgM levels did not differ between patients with and without CAD (70.8 ± 52.7 vs. 69.1 ± 55.1 U/mL). However, anti-PC IgM levels were significantly lower in CAD patients compared to those without vascular remodeling (46.6 ± 31.6 vs. 73.3 ± 58.5 U/mL, P = 0.024). Using multivariate logistic regression, anti-PC IgM plasma levels independently predicted coronary vascular remodeling (HR 0.322, 95% confidence interval 0.121-0.856, P = 0.023). In conclusion, low anti-PC IgM levels are independently associated with coronary vascular remodeling. These findings may represent the link between in vitro studies demonstrating atheroprotective effects of anti-PC IgM and clinical data demonstrating that low anti-PC IgM levels are associated with adverse outcome in CAD patients.

Quantitative assessment of myocardial blush grade in patients with coronary artery disease and in cardiac transplant recipients.

Quantitative assessment of myocardial perfusion by myocardial blush grade (MBG) is an angiographic computer-assisted method to assess myocardial tissue-level reperfusion in patients with acute coronary syndromes and microvascular integrity in heart transplant recipients with suspected cardiac allograft vasculopathy. This review describes the ability of quantitative MBG as a simple, fast and cost effective modality for the prompt diagnosis of impaired microvascular integrity during routine cardiac catheterization. Herein, we summarize the existing evidence, its usefulness in the clinical routine, and compare this method to other techniques which can be used for the assessment of myocardial perfusion.